Secreted and transmembrane polypeptides and nucleic acids encoding the same

ABSTRACT

The present invention is directed to novel polypeptides and to nucleic acid molecules encoding those polypeptides. Also provided herein are vectors and host cells comprising those nucleic acid sequences, chimeric polypeptide molecules comprising the polypeptides of the present invention fused to heterologous polypeptide sequences, antibodies which bind to the polypeptides of the present invention and to methods for producing the polypeptides of the present invention.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This is a continuation application claiming priority under 35 USC§ 120 to U.S. Ser. No. 10/006,867 Filed Dec. 6, 2001, and which claimspriority under 35 USC § 119 to U.S. provisional serial Nos. 60/063,435Filed Oct. 29, 1997; 60/064,215 Filed Oct. 29, 1997; 60/082,797 FiledApr. 22, 1998; 60/083,495 Filed Apr. 29, 1998; 60/085,579 Filed May 15,1998; 60/087,759 Filed Jun. 2, 1998; 60/088,021 Filed Jun. 4, 1998;60/088,029 Filed Jun. 4, 1998; 60/088,030 Filed Jun. 4, 1998; 60/088,734Filed Jun. 10, 1998; 60/088,740 Filed Jun. 10, 1998; 60/088,811 FiledJun. 10, 1998; 60/088,824 Filed Jun. 10, 1998; 60/088,825 Filed Jun. 10,1998; 60/088,863 Filed Jun. 11, 1998; 60/089,105 Filed Jun. 12, 1998;60/089,514 Filed Jun. 16, 1998; 60/089,653 Filed Jun. 17, 1998;60/089,952 Filed Jun. 19, 1998; 60/090,246 Filed Jun. 22, 1998;60/090,444 Filed Jun. 24, 1998; 60/090,688 Filed Jun. 25, 1998;60/090,696 Filed Jun. 25, 1998; 60/090,862 Filed Jun. 26, 1998;60/091,628 Filed Jul. 2, 1998; 60/096,012 Filed Aug. 10, 1998;60/096,757 Filed Aug. 17, 1998; 60/096,949 Filed Aug. 18, 1998;60/096,959 Filed Aug. 18, 1998; 60/097,954 Filed Aug. 26, 1998;60/097,971 Filed Aug. 26, 1998; 60/097,979 Filed Aug. 26, 1998;60/098,749 Filed Sep. 1, 1998; 60/099,741 Filed Sep. 10, 1998;60/099,763 Filed Sep. 10, 1998; 60/099,792 Filed Sep. 10, 1998;60/099,812 Filed Sep. 10, 1998; 60/099,815 Filed Sep. 10, 1998;60/100,627 Filed Sep. 16, 1998; 60/100,662 Filed Sep. 16, 1998;60/100,683 Filed Sep. 17, 1998; 60/100,684 Filed Sep. 17, 1998;60/100,930 Filed Sep. 17, 1998; 60/101,279 Filed Sep. 22, 1998;60/101,475 Filed Sep. 23, 1998; 60/101,738 Filed Sep. 24, 1998;60/101,743 Filed Sep. 24, 1998; 60/101,916 Filed Sep. 24, 1998;60/102,570 Filed Sep. 30, 1998; 60/103,449 Filed Oct. 6, 1998;60/103,678 Filed Oct. 8, 1998; 60/103,679 Filed Oct. 8, 1998; 60/103,711Filed Oct. 8, 1998; 60/105,000 Filed Oct. 20, 1998; 60/105,002 FiledOct. 20, 1998; 60/105,881 Filed Oct. 27, 1998; 60/106,030 Filed Oct. 28,1998; 60/106,464 Filed Oct. 30, 1998; 60/106,856 Filed Nov. 3, 1998;60/108,807 Filed Nov. 17, 1998; 60/112,419 Filed Dec. 15, 1998;60/112,422 Filed Dec. 15, 1998; 60/112,853 Filed Dec. 16, 1998;60/113,011 Filed Dec. 16, 1998; 60/112,854 Filed Dec. 16, 1998;60/113,300 Filed Dec. 22, 1998; 60/113,408 Filed Dec. 22, 1998;60/113,430 Filed Dec. 23, 1998; 60/113,621 Filed Dec. 23, 1998;60/114,223 Filed Dec. 30, 1998; 60/115,614 Filed Jan. 12, 1999;60/116,527 Filed Jan. 20, 1999; 60/116,843 Filed Jan. 22, 1999;60/119,285 Filed Feb. 9, 1999; 60/119,287 Filed Feb. 9, 1999; 60/119,525Filed Feb. 10, 1999; 60/119,549 Filed Feb. 10, 1999; 60/120,014 FiledFeb. 11, 1999; 60/129,122 Filed Apr. 13, 1999; 60/129,674 Filed Apr. 16,1999; 60/131,291 Filed Apr. 27, 1999; 60/138,387 Filed Jun. 9, 1999;60/144,791 Filed Jul. 20, 1999; 60/169,495 Filed Dec. 7, 1999;60/175,481 Filed Jan. 11, 2000; 60/191,007 Filed Mar. 21, 2000;60/199,397 Filed Apr. 25, 2000 and which claims priority under 35 USC §120 to U.S. patent applications and PCT International Patent ApplicationSer. Nos. 09/380,139 Filed Aug. 25, 1999; 09/311,832 Filed May 14, 1999;09/380,137 Filed Aug. 25, 1999, now abandoned; 09/380,138 Filed Aug. 25,1999, now abandoned; 09/380,142 Filed Aug. 25, 1999, now abandoned;09/397,342 Filed Sep. 15, 1999; 09/403,297 Filed Oct. 18, 1999, nowabandoned; 09/423,844 Filed Nov. 12, 1999, now abandoned; 09/644,848Filed Aug. 22, 2000; 09/665,350 Filed Sep. 18, 2000; 09/664,610 FiledSep. 18, 2000, now abandoned; 09/709,238 Filed Nov. 8, 2000; 09/747,259Filed Dec. 20, 2000; 09/816,744 Filed Mar. 22, 2001; 09/854,208 FiledMay 10, 2001; 09/854,280 Filed May 10, 2001; 09/870,574 Filed May 30,2001; 09/874,503 Filed Jun. 5, 2001; 09/908,827 Filed Jul. 18, 2001;09/869,566 Filed Feb. 19, 2002; PCT/US98/19330 Filed Sep. 16, 1998;PCT/US99/05028 Filed Mar. 8, 1999; PCT/US99/10733 Filed May 14, 1999;PCT/US99/12252 Filed Jun. 2, 1999; PCT/US99/20111 Filed Sep. 1, 1999;PCT/US99/21090 Filed Sep. 15, 1999; PCT/US99/21194 Filed Sep. 15, 1999;PCT/US99/30720 Filed Dec. 22, 1999; PCT/US00/04341 Filed Feb. 18, 2000;PCT/US00/04342 Filed Feb. 18, 2000; PCT/US00/04414 Filed Feb. 22, 2000;PCT/US00/05601 Filed Mar. 1, 2000; PCT/US00/08439 Filed Mar. 30, 2000;PCT/US00/14042 Filed May 22, 2000; PCT/US00/15264 Filed Jun. 2, 2000;PCT/US00/23522 Filed Aug. 23, 2000; PCT/US00/23328 Filed Aug. 24, 2000;PCT/US00/30873 Filed Nov. 10, 2000; PCT/US00/32678 Filed Dec. 1, 2000;PCT/US00/34956 Filed Dec. 20, 2000; PCT/US01/06520 Filed Feb. 28, 2001;PCT/US01/06666 Filed Mar. 1, 2001; PCT/US01/17443 Filed May 30, 2001;PCT/US01/17800 Filed Jun. 1, 2001; PCT/US01/19692 Filed Jun. 20, 2001;PCT/US01/21066 Filed Jun. 29, 2001; PCT/US01/21735 Filed Jul. 9, 2001,the entire disclosures of which are hereby incorporated by reference.

BACKGROUND OF THE INVENTION

[0002] The present invention relates generally to the identification andisolation of novel DNA and to the recombinant production of novelpolypeptides.

[0003] Extracellular proteins play important roles in, among otherthings, the formation, differentiation and maintenance of multicellularorganisms. The fate of many individual cells, e.g., proliferation,migration, differentiation, or interaction with other cells, istypically governed by information received from other cells and/or theimmediate environment. This information is often transmitted by secretedpolypeptides (for instance, mitogenic factors, survival factors,cytotoxic factors, differentiation factors, neuropeptides, and hormones)which are, in turn, received and interpreted by diverse cell receptorsor membrane-bound proteins. These secreted polypeptides or signalingmolecules normally pass through the cellular secretory pathway to reachtheir site of action in the extracellular environment.

[0004] Secreted proteins have various industrial applications, includingas pharmaceuticals, diagnostics, biosensors and bioreactors. Mostprotein drugs available at present, such as thrombolytic agents,interferons, interleukins, erythropoietins, colony stimulating factors,and various other cytokines, are secretory proteins. Their receptors,which are membrane proteins, also have potential as therapeutic ordiagnostic agents. Efforts are being undertaken by both industry andacademia to identify new, native secreted proteins. Many efforts arefocused on the screening of mammalian recombinant DNA libraries toidentify the coding sequences for novel secreted proteins. Examples ofscreening methods and techniques are described in the literature [see,for example, Klein et al., Proc. Natl. Acad. Sci. 93:7108-7113 (1996);U.S. Pat. No. 5,536,637)].

[0005] Membrane-bound proteins and receptors can play important rolesin, among other things, the formation, differentiation and maintenanceof multicellular organisms. The fate of many individual cells, e.g.,proliferation, migration, differentiation, or interaction with othercells, is typically governed by information received from other cellsand/or the immediate environment. This information is often transmittedby secreted polypeptides (for instance, mitogenic factors, survivalfactors, cytotoxic factors, differentiation factors, neuropeptides, andhormones) which are, in turn, received and interpreted by diverse cellreceptors or membrane-bound proteins. Such membrane-bound proteins andcell receptors include, but are not limited to, cytokine receptors,receptor kinases, receptor phosphatases, receptors involved in cell-cellinteractions, and cellular adhesin molecules like selectins andintegrins. For instance, transduction of signals that regulate cellgrowth and differentiation is regulated in part by phosphorylation ofvarious cellular proteins. Protein tyrosine kinases, enzymes thatcatalyze that process, can also act as growth factor receptors. Examplesinclude fibroblast growth factor receptor and nerve growth factorreceptor.

[0006] Membrane-bound proteins and receptor molecules have variousindustrial applications, including as pharmaceutical and diagnosticagents. Receptor immunoadhesins, for instance, can be employed astherapeutic agents to block receptor-ligand interactions. Themembrane-bound proteins can also be employed screening of potentialpeptide or small molecule inhibitors of the relevant receptor/ligandinteraction.

[0007] Efforts are being undertaken by both industry and academia toidentify new, native receptor or membrane-bound proteins. Many effortsare focused on the screening of mammalian recombinant DNA libraries toidentify the coding sequences for novel receptor or membrane-boundproteins.

SUMMARY OF INVENTION

[0008] In one embodiment, the invention provides an isolated nucleicacid molecule comprising a nucleotide sequence that encodes a PROpolypeptide.

[0009] In one aspect, the isolated nucleic acid molecule comprises anucleotide sequence having at least about 80% nucleic acid sequenceidentity, alternatively at least about 81% nucleic acid sequenceidentity, alternatively at least about 82% nucleic acid sequenceidentity, alternatively at least about 83% nucleic acid sequenceidentity, alternatively at least about 84% nucleic acid sequenceidentity, alternatively at least about 85% nucleic acid sequenceidentity, alternatively at least about 86% nucleic acid sequenceidentity, alternatively at least about 87% nucleic acid sequenceidentity, alternatively at least about 88% nucleic acid sequenceidentity, alternatively at least about 89% nucleic acid sequenceidentity, alternatively at least about 90% nucleic acid sequenceidentity, alternatively at least about 91% nucleic acid sequenceidentity, alternatively at least about 92% nucleic acid sequenceidentity, alternatively at least about 93% nucleic acid sequenceidentity, alternatively at least about 94% nucleic acid sequenceidentity, alternatively at least about 95% nucleic acid sequenceidentity, alternatively at least about 96% nucleic acid sequenceidentity, alternatively at least about 97% nucleic acid sequenceidentity, alternatively at least about 98% nucleic acid sequenceidentity and alternatively at least about 99% nucleic acid sequenceidentity to (a) a DNA molecule encoding a PRO polypeptide having afull-length amino acid sequence as disclosed herein, an amino acidsequence lacking the signal peptide as disclosed herein, anextracellular domain of a transmembrane protein, with or without thesignal peptide, as disclosed herein or any other specifically definedfragment of the full-length amino acid sequence as disclosed herein, or(b) the complement of the DNA molecule of (a).

[0010] In other aspects, the isolated nucleic acid molecule comprises anucleotide sequence having at least about 80% nucleic acid sequenceidentity, alternatively at least about 81% nucleic acid sequenceidentity, alternatively at least about 82% nucleic acid sequenceidentity, alternatively at least about 83% nucleic acid sequenceidentity, alternatively at least about 84% nucleic acid sequenceidentity, alternatively at least about 85% nucleic acid sequenceidentity, alternatively at least about 86% nucleic acid sequenceidentity, alternatively at least about 87% nucleic acid sequenceidentity, alternatively at least about 88% nucleic acid sequenceidentity, alternatively at least about 89% nucleic acid sequenceidentity, alternatively at least about 90% nucleic acid sequenceidentity, alternatively at least about 91% nucleic acid sequenceidentity, alternatively at least about 92% nucleic acid sequenceidentity, alternatively at least about 93% nucleic acid sequenceidentity, alternatively at least about 94% nucleic acid sequenceidentity, alternatively at least about 95% nucleic acid sequenceidentity, alternatively at least about 96% nucleic acid sequenceidentity, alternatively at least about 97% nucleic acid sequenceidentity, alternatively at least about 98% nucleic acid sequenceidentity and alternatively at least about 99% nucleic acid sequenceidentity to (a) a DNA molecule comprising the coding sequence of afull-length PRO polypeptide cDNA as disclosed herein, the codingsequence of a PRO polypeptide lacking the signal peptide as disclosedherein, the coding sequence of an extracellular domain of atransmembrane PRO polypeptide, with or without the signal peptide, asdisclosed herein or the coding sequence of any other specificallydefined fragment of the full-length amino acid sequence as disclosedherein, or (b) the complement of the DNA molecule of (a).

[0011] In a further aspect, the invention concerns an isolated nucleicacid molecule comprising a nucleotide sequence having at least about 80%nucleic acid sequence identity, alternatively at least about 81% nucleicacid sequence identity, alternatively at least about 82% nucleic acidsequence identity, alternatively at least about 83% nucleic acidsequence identity, alternatively at least about 84% nucleic acidsequence identity, alternatively at least about 85% nucleic acidsequence identity, alternatively at least about 86% nucleic acidsequence identity, alternatively at least about 87% nucleic acidsequence identity, alternatively at least about 88% nucleic acidsequence identity, alternatively at least about 89% nucleic acidsequence identity, alternatively at least about 90% nucleic acidsequence identity, alternatively at least about 91% nucleic acidsequence identity, alternatively at least about 92% nucleic acidsequence identity, alternatively at least about 93% nucleic acidsequence identity, alternatively at least about 94% nucleic acidsequence identity, alternatively at least about 95% nucleic acidsequence identity, alternatively at least about 96% nucleic acidsequence identity, alternatively at least about 97% nucleic acidsequence identity, alternatively at least about 98% nucleic acidsequence identity and alternatively at least about 99% nucleic acidsequence identity to (a) a DNA molecule that encodes the same maturepolypeptide encoded by any of the human protein cDNAs deposited with theATCC as disclosed herein, or (b) the complement of the DNA molecule of(a).

[0012] Another aspect the invention provides an isolated nucleic acidmolecule comprising a nucleotide sequence encoding a PRO polypeptidewhich is either transmembrane domain-deleted or transmembranedomain-inactivated, or is complementary to such encoding nucleotidesequence, wherein the transmembrane domain(s) of such polypeptide aredisclosed herein. Therefore, soluble extracellular domains of the hereindescribed PRO polypeptides are contemplated.

[0013] Another embodiment is directed to fragments of a PRO polypeptidecoding sequence, or the complement thereof, that may find use as, forexample, hybridization probes, for encoding fragments of a PROpolypeptide that may optionally encode a polypeptide comprising abinding site for an anti-PRO antibody or as antisense oligonucleotideprobes. Such nucleic acid fragments are usually at least about 20nucleotides in length, alternatively at least about 30 nucleotides inlength, alternatively at least about 40 nucleotides in length,alternatively at least about 50 nucleotides in length, alternatively atleast about 60 nucleotides in length, alternatively at least about 70nucleotides in length, alternatively at least about 80 nucleotides inlength, alternatively at least about 90 nucleotides in length,alternatively at least about 100 nucleotides in length, alternatively atleast about 110 nucleotides in length, alternatively at least about 120nucleotides in length, alternatively at least about 130 nucleotides inlength, alternatively at least about 140 nucleotides in length,alternatively at least about 150 nucleotides in length, alternatively atleast about 160 nucleotides in length, alternatively at least about 170nucleotides in length, alternatively at least about 180 nucleotides inlength, alternatively at least about 190 nucleotides in length,alternatively at least about 200 nucleotides in length, alternatively atleast about 250 nucleotides in length, alternatively at least about 300nucleotides in length, alternatively at least about 350 nucleotides inlength, alternatively at least about 400 nucleotides in length,alternatively at least about 450 nucleotides in length, alternatively atleast about 500 nucleotides in length, alternatively at least about 600nucleotides in length, alternatively at least about 700 nucleotides inlength, alternatively at least about 800 nucleotides in length,alternatively at least about 900 nucleotides in length and alternativelyat least about 1000 nucleotides in length, wherein in this context theterm “about” means the referenced nucleotide sequence length plus orminus 10% of that referenced length. It is noted that novel fragments ofa PRO polypeptide-encoding nucleotide sequence may be determined in aroutine manner by aligning the PRO polypeptide-encoding nucleotidesequence with other known nucleotide sequences using any of a number ofwell known sequence alignment programs and determining which PROpolypeptide-encoding nucleotide sequence fragment(s) are novel. All ofsuch PRO polypeptide-encoding nucleotide sequences are contemplatedherein. Also contemplated are the PRO polypeptide fragments encoded bythese nucleotide molecule fragments, preferably those PRO polypeptidefragments that comprise a binding site for an anti-PRO antibody.

[0014] In another embodiment, the invention provides isolated PROpolypeptide encoded by any of the isolated nucleic acid sequenceshereinabove identified.

[0015] In a certain aspect, the invention concerns an isolated PROpolypeptide, comprising an amino acid sequence having at least about 80%amino acid sequence identity, alternatively at least about 81% aminoacid sequence identity, alternatively at least about 82% amino acidsequence identity, alternatively at least about 83% amino acid sequenceidentity, alternatively at least about 84% amino acid sequence identity,alternatively at least about 85% amino acid sequence identity,alternatively at least about 86% amino acid sequence identity,alternatively at least about 87% amino acid sequence identity,alternatively at least about 88% amino acid sequence identity,alternatively at least about 89% amino acid sequence identity,alternatively at least about 90% amino acid sequence identity,alternatively at least about 91% amino acid sequence identity,alternatively at least about 92% amino acid sequence identity,alternatively at least about 93% amino acid sequence identity,alternatively at least about 94% amino acid sequence identity,alternatively at least about 95% amino acid sequence identity,alternatively at least about 96% amino acid sequence identity,alternatively at least about 97% amino acid sequence identity,alternatively at least about 98% amino acid sequence identity andalternatively at least about 99% amino acid sequence identity to a PROpolypeptide having a full-length amino acid sequence as disclosedherein, an amino acid sequence lacking the signal peptide as disclosedherein, an extracellular domain of a transmembrane protein, with orwithout the peptide, as disclosed herein or any other specificallydefined fragment of the full-length amino acid sequence as disclosedherein.

[0016] In a further aspect, the invention concerns an isolated PROpolypeptide comprising an amino acid sequence having at least about 80%amino acid sequence identity, alternatively at least about 81% aminoacid sequence identity, alternatively at least about 82% amino acidsequence identity, alternatively at least about 83% amino acid sequenceidentity, alternatively at least about 84% amino acid sequence identity,alternatively at least about 85% amino acid sequence identity,alternatively at least about 86% amino acid sequence identity,alternatively at least about 87% amino acid sequence identity,alternatively at least about 88% amino acid sequence identity,alternatively at least about 89% amino acid sequence identity,alternatively at least about 90% amino acid sequence identity,alternatively at least about 91% amino acid sequence identity,alternatively at least about 92% amino acid sequence identity,alternatively at least about 93% amino acid sequence identity,alternatively at least about 94% amino acid sequence identity,alternatively at least about 95% amino acid sequence identity,alternatively at least about 96% amino acid sequence identity,alternatively at least about 97% amino acid sequence identity,alternatively at least about 98% amino acid sequence identity andalternatively at least about 99% amino acid sequence identity to anamino acid sequence encoded by any of the human protein cDNAs depositedwith the ATCC as disclosed herein.

[0017] In a specific aspect, the invention provides an isolated PROpolypeptide without the N-terminal signal sequence and/or the initiatingmethionine and is encoded by a nucleotide sequence that encodes such anamino acid sequence as hereinbefore described. Processes for producingthe same are also herein described, wherein those processes compriseculturing a host cell comprising a vector which comprises theappropriate encoding nucleic acid molecule under conditions suitable forexpression of the PRO polypeptide and recovering the PRO polypeptidefrom the cell culture.

[0018] Another aspect the invention provides an isolated PRO polypeptidewhich is either transmembrane domain-deleted or transmembranedomain-inactivated. Processes for producing the same are also hereindescribed, wherein those processes comprise culturing a host cellcomprising a vector which comprises the appropriate encoding nucleicacid molecule under conditions suitable for expression of the PROpolypeptide and recovering the PRO polypeptide from the cell culture.

[0019] In yet another embodiment, the invention concerns agonists andantagonists of a native PRO polypeptide as defined herein. In aparticular embodiment, the agonist or antagonist is an anti-PRO antibodyor a small molecule.

[0020] In a further embodiment, the invention concerns a method ofidentifying agonists or antagonists to a PRO polypeptide which comprisecontacting the PRO polypeptide with a candidate molecule and monitoringa biological activity mediated by said PRO polypeptide. Preferably, thePRO polypeptide is a native PRO polypeptide.

[0021] In a still further embodiment, the invention concerns acomposition of matter comprising a PRO polypeptide, or an agonist orantagonist of a PRO polypeptide as herein described, or an anti-PROantibody, in combination with a carrier. Optionally, the carrier is apharmaceutically acceptable carrier.

[0022] Another embodiment of the present invention is directed to theuse of a PRO polypeptide, or an agonist or antagonist thereof ashereinbefore described, or an anti-PRO antibody, for the preparation ofa medicament useful in the treatment of a condition which is responsiveto the PRO polypeptide, an agonist or antagonist thereof or an anti-PROantibody.

[0023] In other embodiments of the present invention, the inventionprovides vectors comprising DNA encoding any of the herein describedpolypeptides. Host cell comprising any such vector are also provided. Byway of example, the host cells may be CHO cells, E. coli, or yeast. Aprocess for producing any of the herein described polypeptides isfurther provided and comprises culturing host cells under conditionssuitable for expression of the desired polypeptide and recovering thedesired polypeptide from the cell culture.

[0024] In other embodiments, the invention provides chimeric moleculescomprising any of the herein described polypeptides fused to aheterologous polypeptide or amino acid sequence. Example of suchchimeric molecules comprise any of the herein described polypeptidesfused to an epitope tag sequence or a Fc region of an immunoglobulin.

[0025] In another embodiment, the invention provides an antibody whichbinds, preferably specifically, to any of the above or below describedpolypeptides. Optionally, the antibody is a monoclonal antibody,humanized antibody, antibody fragment or single-chain antibody.

[0026] In yet other embodiments, the invention provides oligonucleotideprobes useful for isolating genomic and cDNA nucleotide sequences or asantisense probes, wherein those probes may be derived from any of theabove or below described nucleotide sequences.

[0027] In yet other embodiments, the present invention is directed tomethods of using the PRO polypeptides of the present invention for avariety of uses based upon the functional biological assay datapresented in the Examples below.

BRIEF DESCRIPTION OF DRAWINGS

[0028]FIG. 1 shows a nucleotide sequence (SEQ ID NO:1) of a nativesequence PRO180 cDNA, wherein SEQ ID NO:1 is a clone designated hereinas “DNA26843-1389”.

[0029]FIG. 2 shows the amino acid sequence (SEQ ID NO:2) derived fromthe coding sequence of SEQ ID NO:1 shown in FIG. 1.

[0030]FIG. 3 shows a nucleotide sequence (SEQ ID NO:3) of a nativesequence PRO218 cDNA, wherein SEQ ID NO:3 is a clone designated hereinas “DNA30867-1335”.

[0031]FIG. 4 shows the amino acid sequence (SEQ ID NO:4) derived fromthe coding sequence of SEQ ID NO:3 shown in FIG. 3.

[0032]FIG. 5 shows a nucleotide sequence (SEQ ID NO:5) of a nativesequence PRO263 cDNA, wherein SEQ ID NO:5 is a clone designated hereinas “DNA34431-1177”.

[0033]FIG. 6 shows the amino acid sequence (SEQ ID NO:6) derived fromthe coding sequence of SEQ ID NO:5 shown in FIG. 5.

[0034]FIG. 7 shows a nucleotide sequence (SEQ ID NO:7) of a nativesequence PRO295 cDNA, wherein SEQ ID NO:7 is a clone designated hereinas “DNA38268-1188”.

[0035]FIG. 8 shows the amino acid sequence (SEQ ID NO:8) derived fromthe coding sequence of SEQ ID NO:7 shown in FIG. 7.

[0036]FIG. 9 shows a nucleotide sequence (SEQ ID NO:9) of a nativesequence PRO874 cDNA, wherein SEQ ID NO:9 is a clone designated hereinas “DNA40621-1440”.

[0037]FIG. 10 shows the amino acid sequence (SEQ ID NO:10) derived fromthe coding sequence of SEQ ID NO:9 shown in FIG. 9.

[0038]FIG. 11 shows a nucleotide sequence (SEQ ID NO:11) of a nativesequence PRO300 cDNA, wherein SEQ ID NO:11 is a clone designated hereinas “DNA40625-1189”.

[0039]FIG. 12 shows the amino acid sequence (SEQ ID NO:12) derived fromthe coding sequence of SEQ ID NO:11 shown in FIG. 11.

[0040]FIG. 13 shows a nucleotide sequence (SEQ ID NO:13) of a nativesequence PRO1864 cDNA, wherein SEQ ID NO:13 is a clone designated hereinas “DNA45409-2511”.

[0041]FIG. 14 shows the amino acid sequence (SEQ ID NO:14) derived fromthe coding sequence of SEQ ID NO:13 shown in FIG. 13.

[0042]FIG. 15 shows a nucleotide sequence (SEQ ID NO:15) of a nativesequence PRO1282 cDNA, wherein SEQ ID NO:15 is a clone designated hereinas “DNA45495-1550”.

[0043]FIG. 16 shows the amino acid sequence (SEQ ID NO:16) derived fromthe coding sequence of SEQ ID NO:15 shown in FIG. 15.

[0044]FIG. 17 shows a nucleotide sequence (SEQ ID NO:17) of a nativesequence PRO1063 cDNA, wherein SEQ ID NO:17 is a clone designated hereinas “DNA49820-1427”.

[0045]FIG. 18 shows the amino acid sequence (SEQ ID NO:18) derived fromthe coding sequence of SEQ ID NO:17 shown in FIG. 17.

[0046]FIG. 19 shows a nucleotide sequence (SEQ ID NO:19) of a nativesequence PRO1773 cDNA, wherein SEQ ID NO:19 is a clone designated hereinas “DNA56406-1704”.

[0047]FIG. 20 shows the amino acid sequence (SEQ ID NO:20) derived fromthe coding sequence of SEQ ID NO:19 shown in FIG. 19.

[0048]FIG. 21 shows a nucleotide sequence (SEQ ID NO:21) of a nativesequence PRO1013 cDNA, wherein SEQ ID NO:21 is a clone designated hereinas “DNA56410-1414”.

[0049]FIG. 22 shows the amino acid sequence (SEQ ID NO:22) derived fromthe coding sequence of SEQ ID NO:21 shown in FIG. 21.

[0050]FIG. 23 shows a nucleotide sequence (SEQ ID NO:23) of a nativesequence PRO937 cDNA, wherein SEQ ID NO:23 is a clone designated hereinas “DNA56436-1448”.

[0051]FIG. 24 shows the amino acid sequence (SEQ ID NO:24) derived fromthe coding sequence of SEQ ID NO:23 shown in FIG. 23.

[0052]FIG. 25 shows a nucleotide sequence (SEQ ID NO:25) of a nativesequence PRO842 cDNA, wherein SEQ ID NO:25 is a clone designated hereinas “DNA56855-1447”.

[0053]FIG. 26 shows the amino acid sequence (SEQ ID NO:26) derived fromthe coding sequence of SEQ ID NO:25 shown in FIG. 25.

[0054]FIG. 27 shows a nucleotide sequence (SEQ ID NO:27) of a nativesequence PRO1180 cDNA, wherein SEQ ID NO:27 is a clone designated hereinas “DNA56860-1510”.

[0055]FIG. 28 shows the amino acid sequence (SEQ ID NO:28) derived fromthe coding sequence of SEQ ID NO:27 shown in FIG. 27.

[0056]FIG. 29 shows a nucleotide sequence (SEQ ID NO:29) of a nativesequence PRO831 cDNA, wherein SEQ ID NO:29 is a clone designated hereinas “DNA56862-1343”.

[0057]FIG. 30 shows the amino acid sequence (SEQ ID NO:30) derived fromthe coding sequence of SEQ ID NO:29 shown in FIG. 29.

[0058]FIG. 31 shows a nucleotide sequence (SEQ ID NO:31) of a nativesequence PRO1115 cDNA, wherein SEQ ID NO:31 is a clone designated hereinas “DNA56868-1478”.

[0059]FIG. 32 shows the amino acid sequence (SEQ ID NO:32) derived fromthe coding sequence of SEQ ID NO:31 shown in FIG. 31.

[0060]FIG. 33 shows a nucleotide sequence (SEQ ID NO:33) of a nativesequence PRO1277 cDNA, wherein SEQ ID NO:33 is a clone designated hereinas “DNA56869-1545”.

[0061]FIG. 34 shows the amino acid sequence (SEQ ID NO:34) derived fromthe coding sequence of SEQ ID NO:33 shown in FIG. 33.

[0062]FIG. 35 shows a nucleotide sequence (SEQ ID NO:35) of a nativesequence PRO1074 cDNA, wherein SEQ ID NO:35 is a clone designated hereinas “DNA57704-1452”.

[0063]FIG. 36 shows the amino acid sequence (SEQ ID NO:36) derived fromthe coding sequence of SEQ ID NO:35 shown in FIG. 35.

[0064]FIG. 37 shows a nucleotide sequence (SEQ ID NO:37) of a nativesequence PRO1344 cDNA, wherein SEQ ID NO:37 is a clone designated hereinas “DNA58723-1588”.

[0065]FIG. 38 shows the amino acid sequence (SEQ ID NO:38) derived fromthe coding sequence of SEQ ID NO:37 shown in FIG. 37.

[0066]FIG. 39 shows a nucleotide sequence (SEQ ID NO:39) of a nativesequence PRO1136 cDNA, wherein SEQ ID NO:39 is a clone designated hereinas “DNA57827-1493”.

[0067]FIG. 40 shows the amino acid sequence (SEQ ID NO:40) derived fromthe coding sequence of SEQ ID NO:39 shown in FIG. 39.

[0068]FIG. 41 shows a nucleotide sequence (SEQ ID NO:41) of a nativesequence PRO1109 cDNA, wherein SEQ ID NO:41 is a clone designated hereinas “DNA58737-1473”.

[0069]FIG. 42 shows the amino acid sequence (SEQ ID NO:42) derived fromthe coding sequence of SEQ ID NO:41 shown in FIG. 41.

[0070]FIG. 43 shows a nucleotide sequence (SEQ ID NO:43) of a nativesequence PRO1003 cDNA, wherein SEQ ID NO:43 is a clone designated hereinas “DNA58846-1409”.

[0071]FIG. 44 shows the amino acid sequence (SEQ ID NO:44) derived fromthe coding sequence of SEQ ID NO:43 shown in FIG. 43.

[0072]FIG. 45 shows a nucleotide sequence (SEQ ID NO:45) of a nativesequence PRO1138 cDNA, wherein SEQ ID NO:45 is a clone designated hereinas “DNA58850-1495”.

[0073]FIG. 46 shows the amino acid sequence (SEQ ID NO:46) derived fromthe coding sequence of SEQ ID NO:45 shown in FIG. 45.

[0074]FIG. 47 shows a nucleotide sequence (SEQ ID NO:47) of a nativesequence PRO994 cDNA, wherein SEQ ID NO:47 is a clone designated hereinas “DNA58855-1422”.

[0075]FIG. 48 shows the amino acid sequence (SEQ ID NO:48) derived fromthe coding sequence of SEQ ID NO:47 shown in FIG. 47.

[0076]FIG. 49 shows a nucleotide sequence (SEQ ID NO:49) of a nativesequence PRO1069 cDNA, wherein SEQ ID NO:49 is a clone designated hereinas “DNA59211-1450”.

[0077]FIG. 50 shows the amino acid sequence (SEQ ID NO:50) derived fromthe coding sequence of SEQ ID NO:49 shown in FIG. 49.

[0078]FIG. 51 shows a nucleotide sequence (SEQ ID NO:51) of a nativesequence PRO1411 cDNA, wherein SEQ ID NO:51 is a clone designated hereinas “DNA59212-1627”.

[0079]FIG. 52 shows the amino acid sequence (SEQ ID NO:52) derived fromthe coding sequence of SEQ ID NO:51 shown in FIG. 51.

[0080]FIG. 53 shows a nucleotide sequence (SEQ ID NO:53) of a nativesequence PRO1129 cDNA, wherein SEQ ID NO:53 is a clone designated hereinas “DNA59213-1487”.

[0081]FIG. 54 shows the amino acid sequence (SEQ ID NO:54) derived fromthe coding sequence of SEQ ID NO:53 shown in FIG. 53.

[0082]FIG. 55 shows a nucleotide sequence (SEQ ID NO:55) of a nativesequence PRO1027 cDNA, wherein SEQ ID NO:55 is a clone designated hereinas “DNA59605-1418”.

[0083]FIG. 56 shows the amino acid sequence (SEQ ID NO:56) derived fromthe coding sequence of SEQ ID NO:55 shown in FIG. 55.

[0084]FIG. 57 shows a nucleotide sequence (SEQ ID NO:57) of a nativesequence PRO1106 cDNA, wherein SEQ ID NO:57 is a clone designated hereinas “DNA59609-1470”.

[0085]FIG. 58 shows the amino acid sequence (SEQ ID NO:58) derived fromthe coding sequence of SEQ ID NO:57 shown in FIG. 57.

[0086]FIG. 59 shows a nucleotide sequence (SEQ ID NO:59) of a nativesequence PRO1291 cDNA, wherein SEQ ID NO:59 is a clone designated hereinas “DNA59610-1556”.

[0087]FIG. 60 shows the amino acid sequence (SEQ ID NO:60) derived fromthe coding sequence of SEQ ID NO:59 shown in FIG. 59.

[0088]FIG. 61 shows a nucleotide sequence (SEQ ID NO:61) of a nativesequence PRO3573 cDNA, wherein SEQ ID NO:61 is a clone designated hereinas “DNA59837-2545”.

[0089]FIG. 62 shows the amino acid sequence (SEQ ID NO:62) derived fromthe coding sequence of SEQ ID NO:61 shown in FIG. 61.

[0090]FIG. 63 shows a nucleotide sequence (SEQ ID NO:63) of a nativesequence PRO3566 cDNA, wherein SEQ ID NO:63 is a clone designated hereinas “DNA59844-2542”.

[0091]FIG. 64 shows the amino acid sequence (SEQ ID NO:64) derived fromthe coding sequence of SEQ ID NO:63 shown in FIG. 63.

[0092]FIG. 65 shows a nucleotide sequence (SEQ ID NO:65) of a nativesequence PRO1098 cDNA, wherein SEQ ID NO:65 is a clone designated hereinas “DNA59854-1459”.

[0093]FIG. 66 shows the amino acid sequence (SEQ ID NO:66) derived fromthe coding sequence of SEQ ID NO:65 shown in FIG. 65.

[0094]FIG. 67 shows a nucleotide sequence (SEQ ID NO:67) of a nativesequence PRO1158 cDNA, wherein SEQ ID NO:67 is a clone designated hereinas “DNA60625-1507”.

[0095]FIG. 68 shows the amino acid sequence (SEQ ID NO:68) derived fromthe coding sequence of SEQ ID NO:67 shown in FIG. 67.

[0096]FIG. 69 shows a nucleotide sequence (SEQ ID NO:69) of a nativesequence PRO1124 cDNA, wherein SEQ ID NO:69 is a clone designated hereinas “DNA60629-1481”.

[0097]FIG. 70 shows the amino acid sequence (SEQ ID NO:70) derived fromthe coding sequence of SEQ ID NO:69 shown in FIG. 69.

[0098]FIG. 71 shows a nucleotide sequence (SEQ ID NO:71) of a nativesequence PRO1287 cDNA, wherein SEQ ID NO:71 is a clone designated hereinas “DNA61755-1554”.

[0099]FIG. 72 shows the amino acid sequence (SEQ ID NO:72) derived fromthe coding sequence of SEQ ID NO:71 shown in FIG. 71.

[0100]FIG. 73 shows a nucleotide sequence (SEQ ID NO:73) of a nativesequence PRO1335 cDNA, wherein SEQ ID NO:73 is a clone designated hereinas “DNA62812-1594”.

[0101]FIG. 74 shows the amino acid sequence (SEQ ID NO:74) derived fromthe coding sequence of SEQ ID NO:73 shown in FIG. 73.

[0102]FIG. 75 shows a nucleotide sequence (SEQ ID NO:75) of a nativesequence PRO1315 cDNA, wherein SEQ ID NO:75 is a clone designated hereinas “DNA62815-1576”.

[0103]FIG. 76 shows the amino acid sequence (SEQ ID NO:76) derived fromthe coding sequence of SEQ ID NO:75 shown in FIG. 75.

[0104]FIG. 77 shows a nucleotide sequence (SEQ ID NO:77) of a nativesequence PRO1357 cDNA, wherein SEQ ID NO:77 is a clone designated hereinas “DNA64881-1602”.

[0105]FIG. 78 shows the amino acid sequence (SEQ ID NO:78) derived fromthe coding sequence of SEQ ID NO:77 shown in FIG. 77.

[0106]FIG. 79 shows a nucleotide sequence (SEQ ID NO:79) of a nativesequence PRO1356 cDNA, wherein SEQ ID NO:79 is a clone designated hereinas “DNA64886-1601”.

[0107]FIG. 80 shows the amino acid sequence (SEQ ID NO:80) derived fromthe coding sequence of SEQ ID NO:79 shown in FIG. 79.

[0108]FIG. 81 shows a nucleotide sequence (SEQ ID NO:81) of a nativesequence PRO1557 cDNA, wherein SEQ ID NO:81 is a clone designated hereinas “DNA64902-1667”.

[0109]FIG. 82 shows the amino acid sequence (SEQ ID NO:82) derived fromthe coding sequence of SEQ ID NO:81 shown in FIG. 81.

[0110]FIG. 83 shows a nucleotide sequence (SEQ ID NO:83) of a nativesequence PRO1347 cDNA, wherein SEQ ID NO:83 is a clone designated hereinas “DNA64950-1590”.

[0111]FIG. 84 shows the amino acid sequence (SEQ ID NO:84) derived fromthe coding sequence of SEQ ID NO:83 shown in FIG. 83.

[0112]FIG. 85 shows a nucleotide sequence (SEQ ID NO:85) of a nativesequence PRO1302 cDNA, wherein SEQ ID NO:85 is a clone designated hereinas “DNA65403-1565”.

[0113]FIG. 86 shows the amino acid sequence (SEQ ID NO:86) derived fromthe coding sequence of SEQ ID NO:85 shown in FIG. 85.

[0114]FIG. 87 shows a nucleotide sequence (SEQ ID NO:87) of a nativesequence PRO1270 cDNA, wherein SEQ ID NO:87 is a clone designated hereinas “DNA66308-1537”.

[0115]FIG. 88 shows the amino acid sequence (SEQ ID NO:88) derived fromthe coding sequence of SEQ ID NO:87 shown in FIG. 87.

[0116]FIG. 89 shows a nucleotide sequence (SEQ ID NO:89) of a nativesequence PRO1268 cDNA, wherein SEQ ID NO:89 is a clone designated hereinas “DNA66519-1535”.

[0117]FIG. 90 shows the amino acid sequence (SEQ ID NO:90) derived fromthe coding sequence of SEQ ID NO:89 shown in FIG. 89.

[0118]FIG. 91 shows a nucleotide sequence (SEQ ID NO:91) of a nativesequence PRO1327 cDNA, wherein SEQ ID NO:91 is a clone designated hereinas “DNA66521-1583”.

[0119]FIG. 92 shows the amino acid sequence (SEQ ID NO:92) derived fromthe coding sequence of SEQ ID NO:91 shown in FIG. 91.

[0120]FIG. 93 shows a nucleotide sequence (SEQ ID NO:93) of a nativesequence PRO1328 cDNA, wherein SEQ ID NO:93 is a clone designated hereinas “DNA66658-1584”.

[0121]FIG. 94 shows the amino acid sequence (SEQ ID NO:94) derived fromthe coding sequence of SEQ ID NO:93 shown in FIG. 93.

[0122]FIG. 95 shows a nucleotide sequence (SEQ ID NO:95) of a nativesequence PRO1329 cDNA, wherein SEQ ID NO:95 is a clone designated hereinas “DNA66660-1585”.

[0123]FIG. 96 shows the amino acid sequence (SEQ ID NO:96) derived fromthe coding sequence of SEQ ID NO:95 shown in FIG. 95.

[0124]FIG. 97 shows a nucleotide sequence (SEQ ID NO:97) of a nativesequence PRO1340 cDNA, wherein SEQ ID NO:97 is a clone designated hereinas “DNA66663-1598”.

[0125]FIG. 98 shows the amino acid sequence (SEQ ID NO:98) derived fromthe coding sequence of SEQ ID NO:97 shown in FIG. 97.

[0126]FIG. 99 shows a nucleotide sequence (SEQ ID NO:99) of a nativesequence PRO1342 cDNA, wherein SEQ ID NO:99 is a clone designated hereinas “DNA66674-1599”.

[0127]FIG. 100 shows the amino acid sequence (SEQ ID NO:100) derivedfrom the coding sequence of SEQ ID NO:99 shown in FIG. 99.

[0128]FIG. 101 shows a nucleotide sequence (SEQ ID NO:101) of a nativesequence PRO3579 cDNA, wherein SEQ ID NO:101 is a clone designatedherein as “DNA68862-2546”.

[0129]FIG. 102 shows the amino acid sequence (SEQ ID NO:102) derivedfrom the coding sequence of SEQ ID NO:101 shown in FIG. 101.

[0130]FIG. 103 shows a nucleotide sequence (SEQ ID NO:103) of a nativesequence PRO1472 cDNA, wherein SEQ ID NO:103 is a clone designatedherein as “DNA68866-1644”.

[0131]FIG. 104 shows the amino acid sequence (SEQ ID NO:104) derivedfrom the coding sequence of SEQ ID NO:103 shown in FIG. 103.

[0132]FIG. 105 shows a nucleotide sequence (SEQ ID NO:105) of a nativesequence PRO1461 cDNA, wherein SEQ ID NO:105 is a clone designatedherein as “DNA68871-1638”.

[0133]FIG. 106 shows the amino acid sequence (SEQ ID NO:106) derivedfrom the coding sequence of SEQ ID NO:105 shown in FIG. 105.

[0134]FIG. 107 shows a nucleotide sequence (SEQ ID NO:107) of a nativesequence PRO1568 cDNA, wherein SEQ ID NO:107 is a clone designatedherein as “DNA68880-1676”.

[0135]FIG. 108 shows the amino acid sequence (SEQ ID NO:108) derivedfrom the coding sequence of SEQ ID NO:107 shown in FIG. 107.

[0136]FIG. 109 shows a nucleotide sequence (SEQ ID NO:109) of a nativesequence PRO1753 cDNA, wherein SEQ ID NO:109 is a clone designatedherein as “DNA68883-1691”.

[0137]FIG. 110 shows the amino acid sequence (SEQ ID NO:110) derivedfrom the coding sequence of SEQ ID NO:109 shown in FIG. 109.

[0138]FIG. 111 shows a nucleotide sequence (SEQ ID NO:111) of a nativesequence PRO1570 cDNA, wherein SEQ ID NO:111 is a clone designatedherein as “DNA68885-1678”.

[0139]FIG. 112 shows the amino acid sequence (SEQ ID NO:112) derivedfrom the coding sequence of SEQ ID NO:111 shown in FIG. 111.

[0140]FIG. 113 shows a nucleotide sequence (SEQ ID NO:113) of a nativesequence PRO1446 cDNA, wherein SEQ ID NO:113 is a clone designatedherein as “DNA71277-1636”.

[0141]FIG. 114 shows the amino acid sequence (SEQ ID NO:114) derivedfrom the coding sequence of SEQ ID NO:113 shown in FIG. 113.

[0142]FIG. 115 shows a nucleotide sequence (SEQ ID NO:115) of a nativesequence PRO1565 cDNA, wherein SEQ ID NO:115 is a clone designatedherein as “DNA73727-1673”.

[0143]FIG. 116 shows the amino acid sequence (SEQ ID NO:116) derivedfrom the coding sequence of SEQ ID NO:115 shown in FIG. 115.

[0144]FIG. 117 shows a nucleotide sequence (SEQ ID NO:117) of a nativesequence PRO1572 cDNA, wherein SEQ ID NO:117 is a clone designatedherein as “DNA73734-1680”.

[0145]FIG. 118 shows the amino acid sequence (SEQ ID NO:118) derivedfrom the coding sequence of SEQ ID NO:117 shown in FIG. 117.

[0146]FIG. 119 shows a nucleotide sequence (SEQ ID NO:119) of a nativesequence PRO1573 cDNA, wherein SEQ ID NO:119 is a clone designatedherein as “DNA73735-1681”.

[0147]FIG. 120 shows the amino acid sequence (SEQ ID NO:120) derivedfrom the coding sequence of SEQ ID NO:119 shown in FIG. 119.

[0148]FIG. 121 shows a nucleotide sequence (SEQ ID NO:121) of a nativesequence PRO1550 cDNA, wherein SEQ ID NO:121 is a clone designatedherein as “DNA76393-1664”.

[0149]FIG. 122 shows the amino acid sequence (SEQ ID NO:122) derivedfrom the coding sequence of SEQ ID NO:121 shown in FIG. 121.

[0150]FIG. 123 shows a nucleotide sequence (SEQ ID NO:123) of a nativesequence PRO1693 cDNA, wherein SEQ ID NO:123 is a clone designatedherein as “DNA77301-1708”.

[0151]FIG. 124 shows the amino acid sequence (SEQ ID NO:124) derivedfrom the coding sequence of SEQ ID NO:123 shown in FIG. 123.

[0152]FIG. 125 shows a nucleotide sequence (SEQ ID NO:125) of a nativesequence PRO1566 cDNA, wherein SEQ ID NO:125 is a clone designatedherein as “DNA77568-1626”.

[0153]FIG. 126 shows the amino acid sequence (SEQ ID NO:126) derivedfrom the coding sequence of SEQ ID NO:125 shown in FIG. 125.

[0154]FIG. 127 shows a nucleotide sequence (SEQ ID NO:127) of a nativesequence PRO1774 cDNA, wherein SEQ ID NO:127 is a clone designatedherein as “DNA77626-1705”.

[0155]FIG. 128 shows the amino acid sequence (SEQ ID NO:128) derivedfrom the coding sequence of SEQ ID NO:127 shown in FIG. 127.

[0156]FIG. 129 shows a nucleotide sequence (SEQ ID NO:129) of a nativesequence PRO1928 cDNA, wherein SEQ ID NO:129 is a clone designatedherein as “DNA81754-2532”.

[0157]FIG. 130 shows the amino acid sequence (SEQ ID NO:130) derivedfrom the coding sequence of SEQ ID NO:129 shown in FIG. 129.

[0158]FIG. 131 shows a nucleotide sequence (SEQ ID NO:131) of a nativesequence PRO1865 cDNA, wherein SEQ ID NO:131 is a clone designatedherein as “DNA81757-2512”.

[0159]FIG. 132 shows the amino acid sequence (SEQ ID NO:132) derivedfrom the coding sequence of SEQ ID NO:131 shown in FIG. 131.

[0160]FIG. 133 shows a nucleotide sequence (SEQ ID NO:133) of a nativesequence PRO1925 cDNA, wherein SEQ ID NO:133 is a clone designatedherein as “DNA82302-2529”.

[0161]FIG. 134 shows the amino acid sequence (SEQ ID NO:134) derivedfrom the coding sequence of SEQ ID NO:133 shown in FIG. 133.

[0162]FIG. 135 shows a nucleotide sequence (SEQ ID NO:135) of a nativesequence PRO1926 cDNA, wherein SEQ ID NO:135 is a clone designatedherein as “DNA82340-2530”.

[0163]FIG. 136 shows the amino acid sequence (SEQ ID NO:136) derivedfrom the coding sequence of SEQ ID NO:135 shown in FIG. 135.

[0164]FIG. 137 shows a nucleotide sequence (SEQ ID NO:137) of a nativesequence PRO1801 cDNA, wherein SEQ ID NO:137 is a clone designatedherein as “DNA83500-2506”.

[0165]FIG. 138 shows the amino acid sequence (SEQ ID NO:138) derivedfrom the coding sequence of SEQ ID NO:137 shown in FIG. 137.

[0166]FIG. 139 shows a nucleotide sequence (SEQ ID NO:139) of a nativesequence PRO4405 cDNA, wherein SEQ ID NO:139 is a clone designatedherein as “DNA84920-2614”.

[0167]FIG. 140 shows the amino acid sequence (SEQ ID NO:140) derivedfrom the coding sequence of SEQ ID NO:139 shown in FIG. 139.

[0168]FIG. 141 shows a nucleotide sequence (SEQ ID NO:141) of a nativesequence PRO3435 cDNA, wherein SEQ ID NO:141 is a clone designatedherein as “DNA85066-2534”.

[0169]FIG. 142 shows the amino acid sequence (SEQ ID NO:142) derivedfrom the coding sequence of SEQ ID NO:141 shown in FIG. 141.

[0170]FIG. 143 shows a nucleotide sequence (SEQ ID NO:143) of a nativesequence PRO3543 cDNA, wherein SEQ ID NO:143 is a clone designatedherein as “DNA86571-2551”.

[0171]FIG. 144 shows the amino acid sequence (SEQ ID NO:144) derivedfrom the coding sequence of SEQ ID NO:143 shown in FIG. 143.

[0172]FIG. 145 shows a nucleotide sequence (SEQ ID NO:145) of a nativesequence PRO3443 cDNA, wherein SEQ ID NO:145 is a clone designatedherein as “DNA87991-2540”.

[0173]FIG. 146 shows the amino acid sequence (SEQ ID NO:146) derivedfrom the coding sequence of SEQ ID NO:145 shown in FIG. 145.

[0174]FIG. 147 shows a nucleotide sequence (SEQ ID NO:147) of a nativesequence PRO3442 cDNA, wherein SEQ ID NO:147 is a clone designatedherein as “DNA92238-2539”.

[0175]FIG. 148 shows the amino acid sequence (SEQ ID NO:148) derivedfrom the coding sequence of SEQ ID NO:147 shown in FIG. 147.

[0176]FIG. 149 shows a nucleotide sequence (SEQ ID NO:149) of a nativesequence PRO5990 cDNA, wherein SEQ ID NO:149 is a clone designatedherein as “DNA96042-2682”.

[0177]FIG. 150 shows the amino acid sequence (SEQ ID NO:150) derivedfrom the coding sequence of SEQ ID NO:149 shown in FIG. 149.

[0178]FIG. 151 shows a nucleotide sequence (SEQ ID NO:151) of a nativesequence PRO4342 cDNA, wherein SEQ ID NO:151 is a clone designatedherein as “DNA96787-2534”.

[0179]FIG. 152 shows the amino acid sequence (SEQ ID NO:152) derivedfrom the coding sequence of SEQ ID NO:151 shown in FIG. 151.

[0180]FIG. 153 shows a nucleotide sequence (SEQ ID NO:153) of a nativesequence PRO10096 cDNA, wherein SEQ ID NO:153 is a clone designatedherein as “DNA125185-2806”.

[0181]FIG. 154 shows the amino acid sequence (SEQ ID NO:154) derivedfrom the coding sequence of SEQ ID NO:153 shown in FIG. 153.

[0182]FIG. 155 shows a nucleotide sequence (SEQ ID NO:155) of a nativesequence PRO10272 cDNA, wherein SEQ ID NO:155 is a clone designatedherein as “DNA147531-2821”.

[0183]FIG. 156 shows the amino acid sequence (SEQ ID NO:156) derivedfrom the coding sequence of SEQ ID NO:155 shown in FIG. 155.

[0184]FIG. 157 shows a nucleotide sequence (SEQ ID NO:157) of a nativesequence PRO5801 cDNA, wherein SEQ ID NO:157 is a clone designatedherein as “DNA115291-2681”.

[0185]FIG. 158 shows the amino acid sequence (SEQ ID NO:158) derivedfrom the coding sequence of SEQ ID NO:157 shown in FIG. 157.

[0186]FIG. 159 shows a nucleotide sequence (SEQ ID NO:159) of a nativesequence PRO20110 cDNA, wherein SEQ ID NO:159 is a clone designatedherein as “DNA166819”.

[0187]FIG. 160 shows the amino acid sequence (SEQ ID NO:160) derivedfrom the coding sequence of SEQ ID NO:159 shown in FIG. 159.

[0188]FIG. 161 shows a nucleotide sequence (SEQ ID NO:161) of a nativesequence PRO20040 cDNA, wherein SEQ ID NO:161 is a clone designatedherein as “DNA164625-2890”.

[0189]FIG. 162 shows the amino acid sequence (SEQ ID NO:162) derivedfrom the coding sequence of SEQ ID NO:161 shown in FIG. 161.

[0190]FIG. 163 shows a nucleotide sequence (SEQ ID NO:163) of a nativesequence PRO20233 cDNA, wherein SEQ ID NO:163 is a clone designatedherein as “DNA165608”.

[0191]FIG. 164 shows the amino acid sequence (SEQ ID NO:164) derivedfrom the coding sequence of SEQ ID NO:163 shown in FIG. 163.

[0192]FIG. 165 shows a nucleotide sequence (SEQ ID NO:165) of a nativesequence PRO19670 cDNA, wherein SEQ ID NO:165 is a clone designatedherein as “DNA131639-2874”.

[0193]FIG. 166 shows the amino acid sequence (SEQ ID NO:166) derivedfrom the coding sequence of SEQ ID NO:165 shown in FIG. 165.

[0194]FIG. 167 shows a nucleotide sequence (SEQ ID NO:167) of a nativesequence PRO1890 cDNA, wherein SEQ ID NO:167 is a clone designatedherein as “DNA79230-2525”.

[0195]FIG. 168 shows the amino acid sequence (SEQ ID NO:168) derivedfrom the coding sequence of SEQ ID NO:167 shown in FIG. 167.

DETAILED DESCRIPTION 1. Definitions

[0196] The terms “PRO polypeptide” and “PRO” as used herein and whenimmediately followed by a numerical designation refer to variouspolypeptides, wherein the complete designation (i.e., PRO/number) refersto specific polypeptide sequences as described herein. The terms“PRO/number polypeptide” and “PRO/number” wherein the term “number” isprovided as an actual numerical designation as used herein encompassnative sequence polypeptides and polypeptide variants (which are furtherdefined herein). The PRO polypeptides described herein may be isolatedfrom a variety of sources, such as from human tissue types or fromanother source, or prepared by recombinant or synthetic methods. Theterm “PRO polypeptide” refers to each individual PRO/number polypeptidedisclosed herein. All disclosures in this specification which refer tothe “PRO polypeptide” refer to each of the polypeptides individually aswell as jointly. For example, descriptions of the preparation of,purification of, derivation of, formation of antibodies to or against,administration of, compositions containing, treatment of a disease with,etc., pertain to each polypeptide of the invention individually. Theterm “PRO polypeptide” also includes variants of the PRO/numberpolypeptides disclosed herein.

[0197] A “native sequence PRO polypeptide” comprises a polypeptidehaving the same amino acid sequence as the corresponding PRO polypeptidederived from nature. Such native sequence PRO polypeptides can beisolated from nature or can be produced by recombinant or syntheticmeans. The term “native sequence PRO polypeptide” specificallyencompasses naturally-occurring truncated or secreted forms of thespecific PRO polypeptide (e.g., an extracellular domain sequence),naturally-occurring variant forms (e.g., alternatively spliced forms)and naturally-occurring allelic variants of the polypeptide. In variousembodiments of the invention, the native sequence PRO polypeptidesdisclosed herein are mature or full-length native sequence polypeptidescomprising the full-length amino acids sequences shown in theaccompanying figures. Start and stop codons are shown in bold font andunderlined in the figures. However, while the PRO polypeptide disclosedin the accompanying figures are shown to begin with methionine residuesdesignated herein as amino acid position 1 in the figures, it isconceivable and possible that other methionine residues located eitherupstream or downstream from the amino acid position 1 in the figures maybe employed as the starting amino acid residue for the PRO polypeptides.

[0198] The PRO polypeptide “extracellular domain” or “ECD” refers to aform of the PRO polypeptide which is essentially free of thetransmembrane and cytoplasmic domains. Ordinarily, a PRO polypeptide ECDwill have less than 1% of such transmembrane and/or cytoplasmic domainsand preferably, will have less than 0.5% of such domains. It will beunderstood that any transmembrane domains identified for the PROpolypeptides of the present invention are identified pursuant tocriteria routinely employed in the art for identifying that type ofhydrophobic domain. The exact boundaries of a transmembrane domain mayvary but most likely by no more than about 5 amino acids at either endof the domain as initially identified herein. Optionally, therefore, anextracellular domain of a PRO polypeptide may contain from about 5 orfewer amino acids on either side of the transmembranedomain/extracellular domain boundary as identified in the Examples orspecification and such polypeptides, with or without the associatedsignal peptide, and nucleic acid encoding them, are comtemplated by thepresent invention.

[0199] The approximate location of the “signal peptides” of the variousPRO polypeptides disclosed herein are shown in the present specificationand/or the accompanying figures. It is noted, however, that theC-terminal boundary of a signal peptide may vary, but most likely by nomore than about 5 amino acids on either side of the signal peptideC-terminal boundary as initially identified herein, wherein theC-terminal boundary of the signal peptide may be identified pursuant tocriteria routinely employed in the art for identifying that type ofamino acid sequence element (e.g., Nielsen et al., Prot. Eng. 10:1-6(1997) and von Heinje et al., Nucl. Acids. Res. 14:4683-4690 (1986)).Moreover, it is also recognized that, in some cases, cleavage of asignal sequence from a secreted polypeptide is not entirely uniform,resulting in more than one secreted species. These mature polypeptides,where the signal peptide is cleaved within no more than about 5 aminoacids on either side of the C-terminal boundary of the signal peptide asidentified herein, and the polynucleotides encoding them, arecontemplated by the present invention.

[0200] “PRO polypeptide variant” means an active PRO polypeptide asdefined above or below having at least about 80% amino acid sequenceidentity with a full-length native sequence PRO polypeptide sequence asdisclosed herein, a PRO polypeptide sequence lacking the signal peptideas disclosed herein, an extracellular domain of a PRO polypeptide, withor without the signal peptide, as disclosed herein or any other fragmentof a full-length PRO polypeptide sequence as disclosed herein. Such PROpolypeptide variants include, for instance, PRO polypeptides wherein oneor more amino acid residues are added, or deleted, at the N- orC-terminus of the full-length native amino acid sequence. Ordinarily, aPRO polypeptide variant will have at least about 80% amino acid sequenceidentity, alternatively at least about 81% amino acid sequence identity,alternatively at least about 82% amino acid sequence identity,alternatively at least about 83% amino acid sequence identity,alternatively at least about 84% amino acid sequence identity,alternatively at least about 85% amino acid sequence identity,alternatively at least about 86% amino acid sequence identity,alternatively at least about 87% amino acid sequence identity,alternatively at least about 88% amino acid sequence identity,alternatively at least about 89% amino acid sequence identity,alternatively at least about 90% amino acid sequence identity,alternatively at least about 91% amino acid sequence identity,alternatively at least about 92% amino acid sequence identity,alternatively at least about 93% amino acid sequence identity,alternatively at least about 94% amino acid sequence identity,alternatively at least about 95% amino acid sequence identity,alternatively at least about 96% amino acid sequence identity,alternatively at least about 97% amino acid sequence identity,alternatively at least about 98% amino acid sequence identity andalternatively at least about 99% amino acid sequence identity to afull-length native sequence PRO polypeptide sequence as disclosedherein, a PRO polypeptide sequence lacking the signal peptide asdisclosed herein, an extracellular domain of a PRO polypeptide, with orwithout the signal peptide, as disclosed herein or any otherspecifically defined fragment of a full-length PRO polypeptide sequenceas disclosed herein. Ordinarily, PRO variant polypeptides are at leastabout 10 amino acids in length, alternatively at least about 20 aminoacids in length, alternatively at least about 30 amino acids in length,alternatively at least about 40 amino acids in length, alternatively atleast about 50 amino acids in length, alternatively at least about 60amino acids in length, alternatively at least about 70 amino acids inlength, alternatively at least about 80 amino acids in length,alternatively at least about 90 amino acids in length, alternatively atleast about 100 amino acids in length, alternatively at least about 150amino acids in length, alternatively at least about 200 amino acids inlength, alternatively at least about 300 amino acids in length, or more.

[0201] “Percent (%) amino acid sequence identity” with respect to thePRO polypeptide sequences identified herein is defined as the percentageof amino acid residues in a candidate sequence that are identical withthe amino acid residues in the specific PRO polypeptide sequence, afteraligning the sequences and introducing gaps, if necessary, to achievethe maximum percent sequence identity, and not considering anyconservative substitutions as part of the sequence identity. Alignmentfor purposes of determining percent amino acid sequence identity can beachieved in various ways that are within the skill in the art, forinstance, using publicly available computer software such as BLAST,BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the artcan determine appropriate parameters for measuring alignment, includingany algorithms needed to achieve maximal alignment over the full lengthof the sequences being compared. For purposes herein, however, % aminoacid sequence identity values are generated using the sequencecomparison computer program ALIGN-2, wherein the complete source codefor the ALIGN-2 program is provided in Table 1 below. The ALIGN-2sequence comparison computer program was authored by Genentech, Inc. andthe source code shown in Table 1 below has been filed with userdocumentation in the U.S. Copyright Office, Washington D.C., 20559,where it is registered under U.S. Copyright Registration No. TXU510087.The ALIGN-2 program is publicly available through Genentech, Inc., SouthSan Francisco, Calif. or may be compiled from the source code providedin Table 1 below. The ALIGN-2 program should be compiled for use on aUNIX operating system, preferably digital UNIX V4.0D. All sequencecomparison parameters are set by the ALIGN-2 program and do not vary.

[0202] In situations where ALIGN-2 is employed for amino acid sequencecomparisons, the % amino acid sequence identity of a given amino acidsequence A to, with, or against a given amino acid sequence B (which canalternatively be phrased as a given amino acid sequence A that has orcomprises a certain % amino acid sequence identity to, with, or againsta given amino acid sequence B) is calculated as follows:

100 times the fraction X/Y

[0203] where X is the number of amino acid residues scored as identicalmatches by the sequence alignment program ALIGN-2 in that program'salignment of A and B, and where Y is the total number of amino acidresidues in B. It will be appreciated that where the length of aminoacid sequence A is not equal to the length of amino acid sequence B, the% amino acid sequence identity of A to B will not equal the % amino acidsequence identity of B to A. As examples of % amino acid sequenceidentity calculations using this method, Tables 2 and 3 demonstrate howto calculate the % amino acid sequence identity of the amino acidsequence designated “Comparison Protein” to the amino acid sequencedesignated “PRO”, wherein “PRO” represents the amino acid sequence of ahypothetical PRO polypeptide of interest, “Comparison Protein”represents the amino acid sequence of a polypeptide against which the“PRO” polypeptide of interest is being compared, and “X”, “Y” and “Z”each represent different hypothetical amino acid residues.

[0204] Unless specifically stated otherwise, all % amino acid sequenceidentity values used herein are obtained as described in the immediatelypreceding paragraph using the ALIGN-2 computer program. However, % aminoacid sequence identity values may also be obtained as described below byusing the WU-BLAST-2 computer program (Altschul et al., Methods inEnzymology 266:460-480 (1996)). Most of the WU-BLAST-2 search parametersare set to the default values. Those not set to default values, i.e.,the adjustable parameters, are set with the following values: overlapspan=1, overlap fraction=0.125, word threshold (T)=11, and scoringmatrix=BLOSUM62. When WU-BLAST-2 is employed, a % amino acid sequenceidentity value is determined by dividing (a) the number of matchingidentical amino acid residues between the amino acid sequence of the PROpolypeptide of interest having a sequence derived from the native PROpolypeptide and the comparison amino acid sequence of interest (i.e.,the sequence against which the PRO polypeptide of interest is beingcompared which may be a PRO variant polypeptide) as determined byWU-BLAST-2 by (b) the total number of amino acid residues of the PROpolypeptide of interest. For example, in the statement “a polypeptidecomprising an the amino acid sequence A which has or having at least 80%amino acid sequence identity to the amino acid sequence B”, the aminoacid sequence A is the comparison amino acid sequence of interest andthe amino acid sequence B is the amino acid sequence of the PROpolypeptide of interest.

[0205] Percent amino acid sequence identity may also be determined usingthe sequence comparison program NCBI-BLAST2 (Altschul et al., NucleicAcids Res. 25:3389-3402 (1997)). The NCBI-BLAST2 sequence comparisonprogram may be downloaded from http://www.ncbi.nlm.nih.gov or otherwiseobtained from the National Institute of Health, Bethesda, Md.NCBI-BLAST2 uses several search parameters, wherein all of those searchparameters are set to default values including, for example, unmask=yes,strand=all, expected occurrences=10, minimum low complexity length=15/5,multi-pass e-value=0.01, constant for multi-pass=25, dropoff for finalgapped alignment=25 and scoring matrix=BLOSUM62.

[0206] In situations where NCBI-BLAST2 is employed for amino acidsequence comparisons, the % amino acid sequence identity of a givenamino acid sequence A to, with, or against a given amino acid sequence B(which can alternatively be phrased as a given amino acid sequence Athat has or comprises a certain % amino acid sequence identity to, with,or against a given amino acid sequence B) is calculated as follows:

100 times the fraction X/Y

[0207] where X is the number of amino acid residues scored as identicalmatches by the sequence alignment program NCBI-BLAST2 in that program'salignment of A and B, and where Y is the total number of amino acidresidues in B. It will be appreciated that where the length of aminoacid sequence A is not equal to the length of amino acid sequence B, the% amino acid sequence identity of A to B will not equal the % amino acidsequence identity of B to A.

[0208] “PRO variant polynucleotide” or “PRO variant nucleic acidsequence” means a nucleic acid molecule which encodes an active PROpolypeptide as defined below and which has at least about 80% nucleicacid sequence identity with a nucleotide acid sequence encoding afull-length native sequence PRO polypeptide sequence as disclosedherein, a full-length native sequence PRO polypeptide sequence lackingthe signal peptide as disclosed herein, an extracellular domain of a PROpolypeptide, with or without the signal peptide, as disclosed herein orany other fragment of a full-length PRO polypeptide sequence asdisclosed herein. Ordinarily, a PRO variant polynucleotide will have atleast about 80% nucleic acid sequence identity, alternatively at leastabout 81% nucleic acid sequence identity, alternatively at least about82% nucleic acid sequence identity, alternatively at least about 83%nucleic acid sequence identity, alternatively at least about 84% nucleicacid sequence identity, alternatively at least about 85% nucleic acidsequence identity, alternatively at least about 86% nucleic acidsequence identity, alternatively at least about 87% nucleic acidsequence identity, alternatively at least about 88% nucleic acidsequence identity, alternatively at least about 89% nucleic acidsequence identity, alternatively at least about 90% nucleic acidsequence identity, alternatively at least about 91% nucleic acidsequence identity, alternatively at least about 92% nucleic acidsequence identity, alternatively at least about 93% nucleic acidsequence identity, alternatively at least about 94% nucleic acidsequence identity, alternatively at least about 95% nucleic acidsequence identity, alternatively at least about 96% nucleic acidsequence identity, alternatively at least about 97% nucleic acidsequence identity, alternatively at least about 98% nucleic acidsequence identity and alternatively at least about 99% nucleic acidsequence identity with a nucleic acid sequence encoding a full-lengthnative sequence PRO polypeptide sequence as disclosed herein, afull-length native sequence PRO polypeptide sequence lacking the signalpeptide as disclosed herein, an extracellular domain of a PROpolypeptide, with or without the signal sequence, as disclosed herein orany other fragment of a full-length PRO polypeptide sequence asdisclosed herein. Variants do not encompass the native nucleotidesequence.

[0209] Ordinarily, PRO variant polynucleotides are at least about 30nucleotides in length, alternatively at least about 60 nucleotides inlength, alternatively at least about 90 nucleotides in length,alternatively at least about 120 nucleotides in length, alternatively atleast about 150 nucleotides in length, alternatively at least about 180nucleotides in length, alternatively at least about 210 nucleotides inlength, alternatively at least about 240 nucleotides in length,alternatively at least about 270 nucleotides in length, alternatively atleast about 300 nucleotides in length, alternatively at least about 450nucleotides in length, alternatively at least about 600 nucleotides inlength, alternatively at least about 900 nucleotides in length, or more.

[0210] “Percent (%) nucleic acid sequence identity” with respect toPRO-encoding nucleic acid sequences identified herein is defined as thepercentage of nucleotides in a candidate sequence that are identicalwith the nucleotides in the PRO nucleic acid sequence of interest, afteraligning the sequences and introducing gaps, if necessary, to achievethe maximum percent sequence identity. Alignment for purposes ofdetermining percent nucleic acid sequence identity can be achieved invarious ways that are within the skill in the art, for instance, usingpublicly available computer software such as BLAST, BLAST-2, ALIGN orMegalign (DNASTAR) software. For purposes herein, however, % nucleicacid sequence identity values are generated using the sequencecomparison computer program ALIGN-2, wherein the complete source codefor the ALIGN-2 program is provided in Table 1 below. The ALIGN-2sequence comparison computer program was authored by Genentech, Inc. andthe source code shown in Table 1 below has been filed with userdocumentation in the U.S. Copyright Office, Washington D.C., 20559,where it is registered under U.S. Copyright Registration No. TXU510087.The ALIGN-2 program is publicly available through Genentech, Inc., SouthSan Francisco, Calif. or may be compiled from the source code providedin Table 1 below. The ALIGN-2 program should be compiled for use on aUNIX operating system, preferably digital UNIX V4.0D. All sequencecomparison parameters are set by the ALIGN-2 program and do not vary.

[0211] In situations where ALIGN-2 is employed for nucleic acid sequencecomparisons, the % nucleic acid sequence identity of a given nucleicacid sequence C to, with, or against a given nucleic acid sequence D(which can alternatively be phrased as a given nucleic acid sequence Cthat has or comprises a certain % nucleic acid sequence identity to,with, or against a given nucleic acid sequence D) is calculated asfollows:

100 times the fraction W/Z

[0212] where W is the number of nucleotides scored as identical matchesby the sequence alignment program ALIGN-2 in that program's alignment ofC and D, and where Z is the total number of nucleotides in D. It will beappreciated that where the length of nucleic acid sequence C is notequal to the length of nucleic acid sequence D, the % nucleic acidsequence identity of C to D will not equal the % nucleic acid sequenceidentity of D to C. As examples of % nucleic acid sequence identitycalculations, Tables 4 and 5, demonstrate how to calculate the % nucleicacid sequence identity of the nucleic acid sequence designated“Comparison DNA” to the nucleic acid sequence designated “PRO-DNA”,wherein “PRO-DNA” represents a hypothetical PRO-encoding nucleic acidsequence of interest, “Comparison DNA” represents the nucleotidesequence of a nucleic acid molecule against which the “PRO-DNA” nucleicacid molecule of interest is being compared, and “N”, “L” and “V” eachrepresent different hypothetical nucleotides.

[0213] Unless specifically stated otherwise, all % nucleic acid sequenceidentity values used herein are obtained as described in the immediatelypreceding paragraph using the ALIGN-2 computer program. However, %nucleic acid sequence identity values may also be obtained as describedbelow by using the WU-BLAST-2 computer program (Altschul et al., Methodsin Enzymology 266:460-480 (1996)). Most of the WU-BLAST-2 searchparameters are set to the default values. Those not set to defaultvalues, i.e., the adjustable parameters, are set with the followingvalues: overlap span=1, overlap fraction=0.125, word threshold (T)=11,and scoring matrix=BLOSUM62. When WU-BLAST-2 is employed, a % nucleicacid sequence identity value is determined by dividing (a) the number ofmatching identical nucleotides between the nucleic acid sequence of thePRO polypeptide-encoding nucleic acid molecule of interest having asequence derived from the native sequence PRO polypeptide-encodingnucleic acid and the comparison nucleic acid molecule of interest (i.e.,the sequence against which the PRO polypeptide-encoding nucleic acidmolecule of interest is being compared which may be a variant PROpolynucleotide) as determined by WU-BLAST-2 by (b) the total number ofnucleotides of the PRO polypeptide-encoding nucleic acid molecule ofinterest. For example, in the statement “an isolated nucleic acidmolecule comprising a nucleic acid sequence A which has or having atleast 80% nucleic acid sequence identity to the nucleic acid sequenceB”, the nucleic acid sequence A is the comparison nucleic acid moleculeof interest and the nucleic acid sequence B is the nucleic acid sequenceof the PRO polypeptide-encoding nucleic acid molecule of interest.

[0214] Percent nucleic acid sequence identity may also be determinedusing the sequence comparison program NCBI-BLAST2 (Altschul et al.,Nucleic Acids Res. 25:3389-3402 (1997)). The NCBI-BLAST2 sequencecomparison program may be downloaded from http://www.ncbi.nlm.nih.gov orotherwise obtained from the National Institute of Health, Bethesda, Md.NCBI-BLAST2 uses several search parameters, wherein all of those searchparameters are set to default values including, for example, unmask=yes,strand=all, expected occurrences=10, minimum low complexity length=15/5,multi-pass e-value=0.01, constant for multi-pass=25, dropoff for finalgapped alignment=25 and scoring matrix=BLOSUM62.

[0215] In situations where NCBI-BLAST2 is employed for sequencecomparisons, the % nucleic acid sequence identity of a given nucleicacid sequence C to, with, or against a given nucleic acid sequence D(which can alternatively be phrased as a given nucleic acid sequence Cthat has or comprises a certain % nucleic acid sequence identity to,with, or against a given nucleic acid sequence D) is calculated asfollows:

100 times the fraction W/Z

[0216] where W is the number of nucleotides scored as identical matchesby the sequence alignment program NCBI-BLAST2 in that program'salignment of C and D, and where Z is the total number of nucleotides inD. It will be appreciated that where the length of nucleic acid sequenceC is not equal to the length of nucleic acid sequence D, the % nucleicacid sequence identity of C to D will not equal the % nucleic acidsequence identity of D to C.

[0217] In other embodiments, PRO variant polynucleotides are nucleicacid molecules that encode an active PRO polypeptide and which arecapable of hybridizing, preferably under stringent hybridization andwash conditions, to nucleotide sequences encoding a full-length PROpolypeptide as disclosed herein. PRO variant polypeptides may be thosethat are encoded by a PRO variant polynucleotide.

[0218] “Isolated,” when used to describe the various polypeptidesdisclosed herein, means polypeptide that has been identified andseparated and/or recovered from a component of its natural environment.Contaminant components of its natural environment are materials thatwould typically interfere with diagnostic or therapeutic uses for thepolypeptide, and may include enzymes, hormones, and other proteinaceousor non-proteinaceous solutes. In preferred embodiments, the polypeptidewill be purified (1) to a degree sufficient to obtain at least 15residues of N-terminal or internal amino acid sequence by use of aspinning cup sequenator, or (2) to homogeneity by SDS-PAGE undernon-reducing or reducing conditions using Coomassie blue or, preferably,silver stain. Isolated polypeptide includes polypeptide in situ withinrecombinant cells, since at least one component of the PRO polypeptidenatural environment will not be present. Ordinarily, however, isolatedpolypeptide will be prepared by at least one purification step.

[0219] An “isolated” PRO polypeptide-encoding nucleic acid or otherpolypeptide-encoding nucleic acid is a nucleic acid molecule that isidentified and separated from at least one contaminant nucleic acidmolecule with which it is ordinarily associated in the natural source ofthe polypeptide-encoding nucleic acid. An isolated polypeptide-encodingnucleic acid molecule is other than in the form or setting in which itis found in nature. Isolated polypeptide-encoding nucleic acid moleculestherefore are distinguished from the specific polypeptide-encodingnucleic acid molecule as it exists in natural cells. However, anisolated polypeptide-encoding nucleic acid molecule includespolypeptide-encoding nucleic acid molecules contained in cells thatordinarily express the polypeptide where, for example, the nucleic acidmolecule is in a chromosomal location different from that of naturalcells.

[0220] The term “control sequences” refers to DNA sequences necessaryfor the expression of an operably linked coding sequence in a particularhost organism. The control sequences that are suitable for prokaryotes,for example, include a promoter, optionally an operator sequence, and aribosome binding site. Eukaryotic cells are known to utilize promoters,polyadenylation signals, and enhancers.

[0221] Nucleic acid is “operably linked” when it is placed into afunctional relationship with another nucleic acid sequence. For example,DNA for a presequence or secretory leader is operably linked to DNA fora polypeptide if it is expressed as a preprotein that participates inthe secretion of the polypeptide; a promoter or enhancer is operablylinked to a coding sequence if it affects the transcription of thesequence; or a ribosome binding site is operably linked to a codingsequence if it is positioned so as to facilitate translation. Generally,“operably linked” means that the DNA sequences being linked arecontiguous, and, in the case of a secretory leader, contiguous and inreading phase. However, enhancers do not have to be contiguous. Linkingis accomplished by ligation at convenient restriction sites. If suchsites do not exist, the synthetic oligonucleotide adaptors or linkersare used in accordance with conventional practice.

[0222] The term “antibody” is used in the broadest sense andspecifically covers, for example, single anti-PRO monoclonal antibodies(including agonist, antagonist, and neutralizing antibodies), anti-PROantibody compositions with polyepitopic specificity, single chainanti-PRO antibodies, and fragments of anti-PRO antibodies (see below).The term “monoclonal antibody” as used herein refers to an antibodyobtained from a population of substantially homogeneous antibodies,i.e., the individual antibodies comprising the population are identicalexcept for possible naturally-occurring mutations that may be present inminor amounts.

[0223] “Stringency” of hybridization reactions is readily determinableby one of ordinary skill in the art, and generally is an empiricalcalculation dependent upon probe length, washing temperature, and saltconcentration. In general, longer probes require higher temperatures forproper annealing, while shorter probes need lower temperatures.Hybridization generally depends on the ability of denatured DNA toreanneal when complementary strands are present in an environment belowtheir melting temperature. The higher the degree of desired homologybetween the probe and hybridizable sequence, the higher the relativetemperature which can be used. As a result, it follows that higherrelative temperatures would tend to make the reaction conditions morestringent, while lower temperatures less so. For additional details andexplanation of stringency of hybridization reactions, see Ausubel etal., Current Protocols in Molecular Biology, Wiley lntersciencePublishers, (1995).

[0224] “Stringent conditions” or “high stringency conditions”, asdefined herein, may be identified by those that: (1) employ low ionicstrength and high temperature for washing, for example 0.015 M sodiumchloride/0.0015 M sodium citrate/0.1% sodium dodecyl sulfate at 50° C.;(2) employ during hybridization a denaturing agent, such as formamide,for example, 50% (v/v) formamide with 0.1% bovine serum albumin/0.1%Ficoll/0.1% polyvinylpyrrolidone/50 mM sodium phosphate buffer at pH 6.5with 750 mM sodium chloride, 75 mM sodium citrate at 42° C.; or (3)employ 50% formamide, 5×SSC (0.75 M NaCl, 0.075 M sodium citrate), 50 mMsodium phosphate (pH 6.8), 0.1% sodium pyrophosphate, 5× Denhardt'ssolution, sonicated salmon sperm DNA (50 μg/ml), 0.1% SDS, and 10%dextran sulfate at 42° C., with washes at 42° C. in 0.2×SSC (sodiumchloride/sodium citrate) and 50% formamide at 55° C., followed by ahigh-stringency wash consisting of 0.1×SSC containing EDTA at 55° C.

[0225] “Moderately stringent conditions” may be identified as describedby Sambrook et al., Molecular Cloning: A Laboratory Manual, New York:Cold Spring Harbor Press, 1989, and include the use of washing solutionand hybridization conditions (e.g., temperature, ionic strength and %SDS) less stringent that those described above. An example of moderatelystringent conditions is overnight incubation at 37° C. in a solutioncomprising: 20% formamide, 5×SSC (150 mM NaCl, 15 mM trisodium citrate),50 mM sodium phosphate (pH 7.6), 5× Denhardt's solution, 10% dextransulfate, and 20 mg/ml denatured sheared salmon sperm DNA, followed bywashing the filters in 1×SSC at about 37-50° C. The skilled artisan willrecognize how to adjust the temperature, ionic strength, etc. asnecessary to accommodate factors such as probe length and the like.

[0226] The term “epitope tagged” when used herein refers to a chimericpolypeptide comprising a PRO polypeptide fused to a “tag polypeptide”.The tag polypeptide has enough residues to provide an epitope againstwhich an antibody can be made, yet is short enough such that it does notinterfere with activity of the polypeptide to which it is fused. The tagpolypeptide preferably also is fairly unique so that the antibody doesnot substantially cross-react with other epitopes. Suitable tagpolypeptides generally have at least six amino acid residues and usuallybetween about 8 and 50 amino acid residues (preferably, between about 10and 20 amino acid residues).

[0227] As used herein, the term “immunoadhesin” designates antibody-likemolecules which combine the binding specificity of a heterologousprotein (an “adhesin”) with the effector functions of immunoglobulinconstant domains. Structurally, the immunoadhesins comprise a fusion ofan amino acid sequence with the desired binding specificity which isother than the antigen recognition and binding site of an antibody(i.e., is “heterologous”), and an immunoglobulin constant domainsequence. The adhesin part of an immunoadhesin molecule typically is acontiguous amino acid sequence comprising at least the binding site of areceptor or a ligand. The immunoglobulin constant domain sequence in theimmunoadhesin may be obtained from any immunoglobulin, such as IgG-1,IgG-2, IgG-3, or IgG-4 subtypes, IgA (including IgA-1 and IgA-2), IgE,IgD or IgM.

[0228] “Active” or “activity” for the purposes herein refers to form(s)of a PRO polypeptide which retain a biological and/or an immunologicalactivity of native or naturally-occurring PRO, wherein “biological”activity refers to a biological function (either inhibitory orstimulatory) caused by a native or naturally-occurring PRO other thanthe ability to induce the production of an antibody against an antigenicepitope possessed by a native or naturally-occurring PRO and an“immunological” activity refers to the ability to induce the productionof an antibody against an antigenic epitope possessed by a native ornaturally-occurring PRO.

[0229] The term “antagonist” is used in the broadest sense, and includesany molecule that partially or fully blocks, inhibits, or neutralizes abiological activity of a native PRO polypeptide disclosed herein. In asimilar manner, the term “agonist” is used in the broadest sense andincludes any molecule that mimics a biological activity of a native PROpolypeptide disclosed herein. Suitable agonist or antagonist moleculesspecifically include agonist or antagonist antibodies or antibodyfragments, fragments or amino acid sequence variants of native PROpolypeptides, peptides, antisense oligonucleotides, small organicmolecules, etc. Methods for identifying agonists or antagonists of a PROpolypeptide may comprise contacting a PRO polypeptide with a candidateagonist or antagonist molecule and measuring a detectable change in oneor more biological activities normally associated with the PROpolypeptide.

[0230] “Treatment” refers to both therapeutic treatment and prophylacticor preventative measures, wherein the object is to prevent or slow down(lessen) the targeted pathologic condition or disorder. Those in need oftreatment include those already with the disorder as well as those proneto have the disorder or those in whom the disorder is to be prevented.

[0231] “Chronic” administration refers to administration of the agent(s)in a continuous mode as opposed to an acute mode, so as to maintain theinitial therapeutic effect (activity) for an extended period of time.“Intermittent” administration is treatment that is not consecutivelydone without interruption, but rather is cyclic in nature.

[0232] “Mammal” for purposes of treatment refers to any animalclassified as a mammal, including humans, domestic and farm animals, andzoo, sports, or pet animals, such as dogs, cats, cattle, horses, sheep,pigs, goats, rabbits, etc. Preferably, the mammal is human.

[0233] Administration “in combination with” one or more furthertherapeutic agents includes simultaneous (concurrent) and consecutiveadministration in any order.

[0234] “Carriers” as used herein include pharmaceutically acceptablecarriers, excipients, or stabilizers which are nontoxic to the cell ormammal being exposed thereto at the dosages and concentrations employed.Often the physiologically acceptable carrier is an aqueous pH bufferedsolution. Examples of physiologically acceptable carriers includebuffers such as phosphate, citrate, and other organic acids;antioxidants including ascorbic acid; low molecular weight (less thanabout 10 residues) polypeptide; proteins, such as serum albumin,gelatin, or immunoglobulins; hydrophilic polymers such aspolyvinylpyrrolidone; amino acids such as glycine, glutamine,asparagine, arginine or lysine; monosaccharides, disaccharides, andother carbohydrates including glucose, mannose, or dextrins; chelatingagents such as EDTA; sugar alcohols such as mannitol or sorbitol;salt-forming counterions such as sodium; and/or nonionic surfactantssuch as TWEEN™, polyethylene glycol (PEG), and PLURONICS™.

[0235] “Antibody fragments” comprise a portion of an intact antibody,preferably the antigen binding or variable region of the intactantibody. Examples of antibody fragments include Fab, Fab′, F(ab′)₂, andFv fragments; diabodies; linear antibodies (Zapata et al., Protein Eng.8(10): 1057-1062 [1995]); single-chain antibody molecules; andmultispecific antibodies formed from antibody fragments.

[0236] Papain digestion of antibodies produces two identicalantigen-binding fragments, called “Fab” fragments, each with a singleantigen-binding site, and a residual “Fc” fragment, a designationreflecting the ability to crystallize readily. Pepsin treatment yieldsan F(ab′)₂ fragment that has two antigen-combining sites and is stillcapable of cross-linking antigen.

[0237] “Fv” is the minimum antibody fragment which contains a completeantigen-recognition and -binding site. This region consists of a dimerof one heavy- and one light-chain variable domain in tight, non-covalentassociation. It is in this configuration that the three CDRs of eachvariable domain interact to define an antigen-binding site on thesurface of the V_(H)-V_(L) dimer. Collectively, the six CDRs conferantigen-binding specificity to the antibody. However, even a singlevariable domain (or half of an Fv comprising only three CDRs specificfor an antigen) has the ability to recognize and bind antigen, althoughat a lower affinity than the entire binding site.

[0238] The Fab fragment also contains the constant domain of the lightchain and the first constant domain (CH1) of the heavy chain. Fabfragments differ from Fab′ fragments by the addition of a few residuesat the carboxy terminus of the heavy chain CH1 domain including one ormore cysteines from the antibody hinge region. Fab′-SH is thedesignation herein for Fab′ in which the cysteine residue(s) of theconstant domains bear a free thiol group. F(ab′)₂ antibody fragmentsoriginally were produced as pairs of Fab′ fragments which have hingecysteines between them. Other chemical couplings of antibody fragmentsare also known.

[0239] The “light chains” of antibodies (immunoglobulins) from anyvertebrate species can be assigned to one of two clearly distinct types,called kappa and lambda, based on the amino acid sequences of theirconstant domains.

[0240] Depending on the amino acid sequence of the constant domain oftheir heavy chains, immunoglobulins can be assigned to differentclasses. There are five major classes of immunoglobulins: IgA, IgD, IgE,IgG, and IgM, and several of these may be further divided intosubclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA, and IgA2.

[0241] “Single-chain Fv” or “sFv” antibody fragments comprise the V_(H)and V_(L) domains of antibody, wherein these domains are present in asingle polypeptide chain. Preferably, the Fv polypeptide furthercomprises a polypeptide linker between the V_(H) and V_(L) domains whichenables the sFv to form the desired structure for antigen binding. For areview of sFv, see Pluckthun in The Pharmacology of MonoclonalAntibodies, vol.113, Rosenburg and Moore eds., Springer-Verlag, NewYork, pp. 269-315 (1994).

[0242] The term “diabodies” refers to small antibody fragments with twoantigen-binding sites, which fragments comprise a heavy-chain variabledomain (V_(H)) connected to a light-chain variable domain (V_(L)) in thesame polypeptide chain (V_(H)-V_(L)). By using a linker that is tooshort to allow pairing between the two domains on the same chain, thedomains are forced to pair with the complementary domains of anotherchain and create two antigen-binding sites. Diabodies are described morefully in, for example, EP 404,097; WO 93/11161; and Hollinger et al.,Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993).

[0243] An “isolated” antibody is one which has been identified andseparated and/or recovered from a component of its natural environment.Contaminant components of its natural environment are materials whichwould interfere with diagnostic or therapeutic uses for the antibody,and may include enzymes, hormones, and other proteinaceous ornonproteinaceous solutes. In preferred embodiments, the antibody will bepurified (1) to greater than 95% by weight of antibody as determined bythe Lowry method, and most preferably more than 99% by weight, (2) to adegree sufficient to obtain at least 15 residues of N-terminal orinternal amino acid sequence by use of a spinning cup sequenator, or (3)to homogeneity by SDS-PAGE under reducing or nonreducing conditionsusing Coomassie blue or, preferably, silver stain. Isolated antibodyincludes the antibody in situ within recombinant cells since at leastone component of the antibody's natural environment will not be present.Ordinarily, however, isolated antibody will be prepared by at least onepurification step.

[0244] An antibody that “specifically binds to” or is “specific for” aparticular polypeptide or an epitope on a particular polypeptide is onethat binds to that particular polypeptide or epitope on a particularpolypeptide without substantially binding to any other polypeptide orpolypeptide epitope.

[0245] The word “label” when used herein refers to a detectable compoundor composition which is conjugated directly or indirectly to theantibody so as to generate a “labeled” antibody. The label may bedetectable by itself (e.g. radioisotope labels or fluorescent labels)or, in the case of an enzymatic label, may catalyze chemical alterationof a substrate compound or composition which is detectable.

[0246] By “solid phase” is meant a non-aqueous matrix to which theantibody of the present invention can adhere. Examples of solid phasesencompassed herein include those formed partially or entirely of glass(e.g., controlled pore glass), polysaccharides (e.g., agarose),polyacrylamides, polystyrene, polyvinyl alcohol and silicones. Incertain embodiments, depending on the context, the solid phase cancomprise the well of an assay plate; in others it is a purificationcolumn (e.g., an affinity chromatography column). This term alsoincludes a discontinuous solid phase of discrete particles, such asthose described in U.S. Pat. No. 4,275,149.

[0247] A “liposome” is a small vesicle composed of various types oflipids, phospholipids and/or surfactant which is useful for delivery ofa drug (such as a PRO polypeptide or antibody thereto) to a mammal. Thecomponents of the liposome are commonly arranged in a bilayer formation,similar to the lipid arrangement of biological membranes.

[0248] A “small molecule” is defined herein to have a molecular weightbelow about 500 Daltons TABLE 1 /*  *  * C—C increased from 12 to 15  *Z is average of EQ  * B is average of ND  * match with stop is _M;stop—stop = 0; J (joker) match = 0  */ #define _M −8 /* value of a matchwith a stop */ int _day[26][26] = { /*  A B C D E F G H I J K L M N O PQ R S T U V W X Y Z */ /* A */ {2, 0, −2, 0, 0, −4, 1, −1, −1, 0, −1,−2, −1, 0, _M, 1, 0, −2, 1, 1, 0, 0, −6, 0, −3, 0}, /* B */ {0, 3, −4,3, 2, −5, 0, 1, −2, 0, 0, −3, −2, 2, _M, −1, 1, 0, 0, 0, 0, −2, −5, 0,−3, 1}, /* C */ {−2, −4, 15, −5, −5, −4, −3, −3, −2, 0, −5, −6, −5, −4,_M, −3, −5, −4, 0, −2, 0, −2, −8, 0, 0, −5}, /* D */ {0, 3, −5, 4, 3,−6, 1, 1, −2, 0, 0, −4, −3, 2, _M, −1, 2, −1, 0, 0, 0, −2, −7, 0, −4,2}, /* E */ {0, 2, −5, 3, 4, −5, 0, 1, −2, 0, 0, −3, −2, 1, _M, −1, 2,−1, 0, 0, 0, −2, −7, 0, −4, 3}, /* F */ {−4, −5, −4, −6, −5, 9, −5, −2,1, 0, −5, 2, 0, −4, _M, −5, −5, −4, −3, −3, 0, −1, 0, 0, 7, −5}, /* G */{1, 0, −3, 1, 0, −5, 5, −2, −3, 0, −2, −4, −3, 0, _M, −1, −1, −3, 1, 0,0, −1, −7, 0, −5, 0}, /* H */ {−1, 1, −3, 1, 1, −2, −2, 6, −2, 0, 0, −2,−2, 2, _M, 0, 3, 2, −1, −1, 0, −2, −3, 0, 0, 2}, /* I */ {−1, −2, −2,−2, −2, 1, −3, −2, 5, 0, −2, 2, 2, −2, _M, −2, −2, −2, −1, 0, 0, 4, −5,0, −1, −2}, /* J */ {0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, _M, 0, 0,0, 0, 0, 0, 0, 0, 0, 0, 0}, /* K */ {−1, 0, −5, 0, 0, −5, −2, 0, −2, 0,5, −3, 0, 1, _M, −1, 1, 3, 0, 0, 0, −2, −3, 0, −4, 0}, /* L */ {−2, −3,−6, −4, −3, 2, −4, −2, 2, 0, −3, 6, 4, −3, _M, −3, −2, −3, −3 , −1, 0,2, −2, 0, −1, −2} /* M */ {−1, −2, −5, −3, −2, 0, −3, −2, 2, 0, 0, 4, 6,−2, _M, −2, −1, 0, −2, −1, 0, 2, −4, 0, −2, −1}, /* N */ {0, 2, −4, 2,1, −4, 0, 2, −2, 0, 1, −3, −2, 2, _M, −1, 1, 0, 1, 0, 0, −2, −4, 0, −2,1}, /* O */ {_M,_M,_M,_M,_M,_M,_M,_M,_M,_M,_M,_M,_M,_M,0,_M,_M,_M,_M,_M,_M,_M,_M,_M,_M,_M,}, /* P */ {1, −1, −3, −1, −1, −5,−1, 0, −2, 0, −1, −3, −2, −1,_M, 6, 0, 0, 1, 0, 0, −1, −6, 0, −5, 0}, /*Q */ {0, 1, −5, 2, 2, −5, −1, 3, −2, 0, 1, −2, −1, 1, _M, 0, 4, 1, −1,−1, 0, −2, −5, 0, −4, 3}, /* R */ {−2, 0, −4, −1, −1, −4, −3, 2, −2, 0,3, −3, 0, 0, _M, 0, 1, 6, 0, −1, 0, −2, 2, 0, −4, 0}, /* S */ {1, 0, 0,0, 0, −3, 1, −1, −1, 0, 0, −3, −2, 1, _M, 1, −1, 0, 2, 1, 0, −1, −2, 0,−3, 0}, /* T */ {1, 0, −2, 0, 0, −3, 0, −1, 0, 0, 0, −1, −1, 0, _M, 0,−1, −1, 1, 3, 0, 0, −5, 0, −3, 0}, /* U */ {0, 0, 0, 0, 0, 0, 0, 0, 0,0, 0, 0, 0, 0,_M, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0}, /* V */ {0, −2, −2,−2, −2, −1, −1, −2, 4, 0, −2, 2, 2, −2,_M, −1, −2, −2, −1, 0, 0, 4, −6,0, −2, −2}, /* W */ {−6, −5, −8, −7, −7, 0, −7, −3, −5, 0, −3, −2, −4,−4,_M, −6, −5, 2, −2, −5, 0, −6, 17, 0, 0, −6}, /* X */ {0, 0, 0, 0, 0,0, 0, 0, 0, 0, 0, 0, 0, 0, _M, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0}, /* Y */{−3, −3, 0, −4, −4, 7, −5, 0, −1, 0, −4, −1, −2, −2, _M, −5, −4, −4, −3,−3, 0, −2, 0, 0, 10, −4}, /* Z */ {0, 1, −5, 2, 3, −5, 0, 2, −2, 0, 0,−2, −1, 1,_M, 0, 3, 0, 0, 0, 0, −2, −6, 0, −4, 4}, }; /*  */ #include<stdio.h> #include <ctype.h> #define MAXJMP  16 /* max jumps in a diag*/ #define MAXGAP  24 /* don't continue to penalize gaps larger thanthis */ #define JMPS 1024 /* max jmps in an path */ #define MX   4 /*save if there's at least MX-1 bases since last jmp */ #define DMAT   3/* value of matching bases */ #define DMIS   0 /* penalty for mismatchedbases */ #define DINS0   8 /* penalty for a gap */ #define DINS1   1 /*penalty per base */ #define PINS0   8 /* penalty for a gap */ #definePINS1   4 /* penalty per residue */ struct jmp { short n[MAXJMP]; /*size of jmp (neg for dely) */ unsigned short x[MAXJMP]; /* base no. ofjmp in seq x */ /* limits seq to 2{circumflex over ( )}16 −1 */ };struct diag { int score; /* score at last jmp */ long offset; /* offsetof prev block */ short ijmp; /* current jmp index */ struct jmp jp; /*list of jmps */ }; struct path { int spc; /* number of leading spaces */short n[JMPS]; /* size of jmp (gap) */ int x[JMPS]; /* loc of jmp (lastelem before gap) */ }; char *ofile; /* output file name */ char*namex[2]; /* seq names: getseqs() */ char *prog; /* prog name for errmsgs */ char *seqx[2]; /* seqs: getseqs() */ int dmax; /* best diag:nw() */ int dmax0; /* final diag */ int dna; /* set if dna: main() */int endgaps; /* set if penalizing end gaps */ int gapx, gapy; /* totalgaps in seqs */ int len0, len1; /* seq lens */ int ngapx, ngapy; /*total size of gaps */ int smax; /* max score: nw() */ int *xbm; /*bitmap for matching */ long offset; /* current offset in jmp file */struct diag *dx; /* holds diagonals */ struct path pp[2]; /* holds pathfor seqs */ char *calloc(), *malloc(), *index(), *strcpy(); char*getseq(), *g_calloc(); /* Needleman-Wunsch alignment program  *  *usage: progs file1 file2  *  where file1 and file2 are two dna or twoprotein sequences.  *  The sequences can be in upper- or lower-case anmay contain ambiguity  *  Any lines beginning with ‘;’, ‘>’ or ‘<’ areignored  *  Max file length is 65535 (limited by unsigned short x in thejmp struct)  *  A sequence with ⅓ or more of its elements ACGTU isassumed to be DNA  *  Output is in the file “align.out”  *  * Theprogram may create a tmp file in /tmp to hold info about traceback.  *Original version developed under BSD 4.3 on a vax 8650  */ #include“nw.h” #include “day.h” static _dbval[26] = {1,14,2,13,0,0,4,11,0,0,12,0,3,15,0,0,0,5,6,8,8,7,9,0,10,0 }; static_pbval[26] = { 1, 2|(1<<(‘D’-‘A’))|(1<<(‘N’-‘A’)), 4, 8, 16, 32, 64,128, 256, 0×FFFFFFF, 1<<10, 1<<11, 1<<12, 1<<13, 1<<14, 1<<15, 1<<16, 1<<17, 1<<18, 1<<19, 1<<20, 1<<21, 1<<22, 1<<23, 1<<24,1<<25|(1<<(‘E’-‘A’))|(1<<(‘Q’-‘A’)) }; main(ac, av) main int ac; char*av[]; { prog = av[0]; if(ac != 3) { fprintf(stderr, “usage: %s file1file2\n”, prog); fprintf(stderr, “where file1 and file2 are two dna ortwo protein sequences.\n”); fprintf(stderr, “The sequences can be inupper- or lower-case\n”); fprintf(stderr, “Any lines beginning with ‘;’or ‘<’ are ignored\n”); fprintf(stderr, “Output is in the file\“align.out\”\n”); exit(1); } namex[0] = av[1]; namex[1] = av[2];seqx[0] = getseq(namex[0], &len0); seqx[1] = getseq(namex[1], &len1);xbm = (dna)? _dbval : _pbval; endgaps = 0; /* 1 to penalize endgaps */ofile = “align.out”; /* output file */ nw(); /* fill in the matrix, getthe possible jmps */ readjmps(); /* get the actual jmps */ print(); /*print stats, alignment */ cleanup(0); /* unlink any tmp files */ } /* dothe alignment, return best score: main()  * dna: values in Fitch andSmith, PNAS, 80, 1382-1386, 1983  * pro: PAM 250 values  * When scoresare equal, we prefer mismatches to any gap, prefer  * a new gap toextending an ongoing gap, and prefer a gap in seqx  * to a gap in seq y. */ nw() nw { char *px, *py; /* seqs and ptrs */ int *ndely, *dely; /*keep track of dely */ int ndelx, delx; /* keep track of delx */ int*tmp; /* for swapping row0, row1 */ int mis; /* score for each type */int ins0, ins1; /* insertion penalties */ register id; /* diagonal index*/ register ij; /* jmp index */ register *col0, *col1; /* score forcurr, last row */ register xx, yy; /* index into seqs */ dx = (structdiag *)g_calloc(“to get diags”, len0+len1+1, sizeof(struct diag)); ndely= (int *)g_calloc(“to get ndely”, len1+1, sizeof(int)); dely = (int*)g_calloc(“to get dely”, len1+1, sizeof(int)); col0 = (int*)g_calloc(“to get col0”, len1+1, sizeof(int)); col1 = (int*)g_calloc(“to get col1”, len1+1, sizeof(int)); ins0 = (dna)? DINS0 :PINS0; ins1 = (dna)? DINS1 : PlNS1; smax = −10000; if (endgaps) { for(col0[0] = dely[0] = −ins0, yy = 1; yy <= len1; yy++) { col0[yy] =dely[yy] = col0[yy−1] − ins1; ndely[yy] = yy; } col0[0] = 0; /* WatermanBull Math Biol 84 */ } else for (yy = 1; yy <= len1; yy++) dely[yy] =−ins0; /* fill in match matrix  */ for (px = seqx[0], xx = 1; xx <=len0; px++, xx++) { /* initialize first entry in col  */ if (endgaps) {if (xx == 1) col1[0] = delx = −(ins0+ins1); else col1[0] = delx =col0[0]−ins1; ndelx = xx; } else { col1[0] = 0; delx = −ins0; ndelx = 0;} ...nw for (py = seqx[1], yy = 1; yy <= len1; py++, yy++) { mis =col0[yy−1]; if (dna) mis += (xbm[*px−‘A’]&xbm[*py−‘A’])? DMAT : DMIS;else mis += _day[*px−‘A’][*py−‘A’]; /* update penalty for del in x seq; * favor new del over ongong del  * ignore MAXGAP if weighting endgaps */ if (endgaps || ndely[yy] < MAXGAP) { if (col0[yy] − ins0 >=dely[yy]) { dely[yy] = col0[yy] − (ins0+ins1); ndely[yy] = 1; } else {dely[yy] −= ins1; ndely[yy]++; } } else { if (col0[yy] − (ins0+ins1) >=dely[yy]) { dely[yy] = col0[yy] − (ins0+ins1); ndely[yy] = 1; } elsendely[yy]++; } /* update penalty for del in y seq;  * favor new del overongong del  */ if (endgaps || ndelx < MAXGAP) { if(col1[yy−1] − ins0 >=delx) { delx = col1[yy−1] − (ins0+ins1); ndelx = 1; } else { delx −=ins1; ndelx++; } } else { if (col1[yy−1] − (ins0+ins1) >= delx) { delx =col1[yy−1] − (ins0+ins1); ndelx = 1; } else ndelx++; } /* pick themaximum score; we're favoring  * mis over any del and delx over dely  */...nw id = xx − yy + len1 − 1; if (mis >= delx && mis >= dely[yy])col1[yy] = mis; else if (delx >= dely[yy]) { col1[yy] = delx; ij =dx[id].ijmp; if (dx[id].jp.n[0] && (!dna || (ndelx >= MAXJMP && xx >dx[id].jp.x[ij]+MX) || mis > dx[id].score+DINS0)) { dx[id].ijmp++; if(++ij >= MAXJMP) { writejmps(id); ij = dx[id].ijmp = 0; dx[id].offset =offset; offset += sizeof(struct jmp) + sizeof(offset); } }dx[id].jp.n[ij] = ndelx; dx[id].jp.x[ij] = xx; dx[id].score = delx; }else { col1[yy] = dely[yy]; ij = dx[id].ijmp; if (dx[id].jp.n[0] &&(!dna || (ndely[yy] >= MAXJMP && xx > dx[id].jp.x[ij]+MX) || mis >dx[id].score+DINS0)) { dx[id].ijmp++; if (++ij >= MAXJMP) {writejmps(id); ij = dx[id].ijmp = 0; dx[id].offset = offset; offset +=sizeof(struct jmp) + sizeof(offset); } } dx[id].jp.n[ij] =− ndely[yy];dx[id].jp.x[ij] = xx; dx[id].score = dely[yy]; } if (xx == len0 && yy <len1) { /* last col  */ if (endgaps) col1[yy] −= ins0+ins1*(len1−yy);if(col1[yy] > smax) { smax = col1[yy]; dmax = id; } } } if (endgaps &&xx < len0) col1[yy−1] −= ins0+ins1*(len0−xx); if (col1[yy−1] > smax) {smax = col1[yy−1]; dmax = id; } tmp = col0; col0 = col1; col1 = tmp; }(void) free((char *)ndely); (void) free((char *)dely); (void) free((char*)col0); (void) free((char *)col1); } /*  *  * print() -- only routinevisible outside this module  *  * static:  * getmat() -- trace back bestpath, count matches: print()  * pr_align() -- print alignment ofdescribed in array p[]: print()  * dumpblock() -- dump a block of lineswith numbers, stars: pr_align()  * nums() -- put out a number line:dumpblock()  * putline() -- put out a line (name, [num], seq, [num]):dumpblock()  * stars() - -put a line of stars: dumpblock()  *stripname() -- strip any path and prefix from a seqname  */ #include“nw.h” #define SPC  3 #define P_LINE 256 /* maximum output line */#define P_SPC  3 /* space between name or num and seq */ extern_day[26][26]; int olen; /* set output line length */ FILE *fx; /* outputfile */ print() print { int lx, ly, firstgap, lastgap;  /* overlap */ if((fx = fopen(ofile, “w”)) == 0) { fprintf(stderr, “%s: can't write%s\n”, prog, ofile); cleanup(1); } fprintf(fx, “<first sequence: %s(length = %d)\n”, namex[0], len0); fprintf(fx, “<second sequence: %s(length = %d)\n”, namex[1], len1); olen = 60; lx = len0; ly = len1;firstgap = lastgap = 0; if (dmax < len1 − 1) { /* leading gap in x */pp[0].spc = firstgap = len1 − dmax − 1; ly −= pp[0].spc; } else if(dmax > len1 − 1) { /* leading gap in y */ pp[1].spc = firstgap = dmax −(len1 − 1); lx −= pp[1].spc; } if (dmax0 < len0 − 1) { /* trailing gapin x */ lastgap = len0 − dmax0 −1; lx −= lastgap; } else if (dmax0 >len0 − 1) { /* trailing gap in y */ lastgap = dmax0 − (len0 − 1); ly −=lastgap; } getmat(lx, ly, firstgap, lastgap); pr_align(); } /*  * traceback the best path, count matches  */ static getmat(lx, ly, firstgap,lastgap) getmat int lx, ly; /* “core” (minus endgaps) */ int firstgap,lastgap; /* leading trailing overlap */ { int nm, i0, i1, siz0, siz1;char outx[32]; double pct; register n0, n1; register char *p0, *p1; /*get total matches, score  */ i0 = i1 = siz0 = siz1 = 0; p0 = seqx[0] +pp[1].spc; p1 = seqx[1] + pp[0].spc; n0 = pp[1].spc + 1; n1 =pp[0].spc + 1; nm = 0; while ( *p0 && *p1 ) { if (siz0) { p1++; n1++;siz0−−; } else if (siz1) { p0++; n0++; siz1−−; } else { if(xbm[*p0−‘A’]&xbm[*p1−‘A’]) nm++; if (n0++ == pp[0].x[i0]) siz0 =pp[0].n[i0++]; if (nl++ == pp[1].x[i1]) siz1 = pp[1].n[il++]; p0++;p1++; } } /* pct homology:  * if penalizing endgaps, base is the shorterseq  * else, knock off overhangs and take shorter core  */ if (endgaps)lx = (len0 < len1)? len0 : len1; else lx = (lx < ly)? lx : ly; pct =100.*(double)nm/(double)lx; fprintf(fx, “\n”); fprintf(fx, “<%d match%sin an overlap of %d: %.2f percent similarity\n”, nm, (nm == 1)? “” :“es”, lx, pct); fprintf(fx, “<gaps in first sequence: %d”, gapx);...getmat if (gapx) { (void) sprintf(outx, “(%d %s%s)”, ngapx, (dna)?“base”: “residue”, (ngapx == 1)? “”:“s”); fprintf(fx, “%s”, outx);fprintf(fx, “, gaps in second sequence: %d”, gapy); if (gapy) { (void)sprintf(outx, “(%d %s%s)”, ngapy, (dna)? “base”:“residue”, (ngapy == 1)?“”:“s”); fprintf(fx, “%s”, outx); } if (dna) fprintf(fx, “\n<score: %d(match = %d, mismatch = %d, gap penalty = %d + %d per base)\n”, smax,DMAT, DMIS, DINS0, DINS1); else fprintf(fx, “\n<score: %d (Dayhoff PAM250 matrix, gap penalty = %d + %d per residue)\n”, smax, PINS0, PINS1);if (endgaps) fprintf(fx, “<endgaps penalized. left endgap: %d %s%s,right endgap: %d %s%s\n”, firstgap, (dna)? “base” : “residue”, (firstgap== 1)? “” : “s”, lastgap, (dna)? “base” : “residue”, (lastgap == 1)? “”: “s”); else fprintf(fx, “<endgaps not penalized\n”); } static nm; /*matches in core -- for checking */ static lmax; /* lengths of strippedfile names */ static ij[2]; /* jmp index for a path */ static nc[2]; /*number at start of current line */ static ni[2]; /* current elem number-- for gapping */ static siz[2]; static char *ps[2]; /* ptr to currentelement */ static char *po[2]; /* ptr to next output char slot */ staticchar out[2][P_LINE]; /* output line */ static char star[P_LINE]; /* setby stars() */ /*  * print alignment of described in struct path pp[]  */static pr_align() pr_align { int nn; /* char count */ int more; registeri; for (i = 0, lmax = 0; i < 2;i++) { nn = stripname(namex[i]); if (nn >lmax) lmax = nn; nc[i] = 1; ni[i] = 1; siz[i] = ij[i] = 0; ps[i] =seqx[i]; po[i] = out[i]; } for (nn = nm = 0, more = 1; more;) {...pr_align for (i = more = 0; i < 2; i++) { /*  * do we have more ofthis sequence?  */ if (!*ps[i]) continue; more++; if (pp[i].spc) { /*leading space */ *po[i]++ = ‘ ’; pp[i].spc−−; } else if (siz[i]) { /* ina gap */ *po[i]++ = ‘−’; siz[i]−−; } else { /* we're putting a seqelement */ *po[i] = *ps[i]; if (islower(*ps[i]))    *ps[i] =toupper(*ps[i]); po[i]++; ps[i]++; /*  * are we at next gap for thisseq?  */ if (ni[i] == pp[i].x[ij[i]]) { /*  * we need to merge all gaps * at this location  */ siz[i] == pp[i].n[ij[i]++]; while (ni[i] ==pp[i].x[ij[i]]) siz[i] += pp[i].n[ij[i]++]; } ni[i]++; } } if (++nn ==olen || !more && nn) { dumpblock(); for (i = 0; i < 2; i++) po[i] =out[i]; nn = 0; } } } /*  * dump a block of lines, including numbers,stars: pr_align()  */ static dumpblock() dumpblock { register i; for(i =0; i < 2; i++) *po[i]−− = ‘\0’; ...dumpblock (void) putc(‘\n’, fx); for(i = 0; i < 2; i++) { if (*out[i] && (*out[i] != ‘ ’ || *(po[i]) != ‘’)) { if (i == 0) nums(i); if (i == 0 && *out[1]) stars(); putline(i);if (i == 0 && *out[1]) fprintf(fx, star); if (i == 1) nums(i); } } }/* * put out a number line: dumpblock()  */ static nums(ix) numsint  ix; /* index in out[] holding seq line */ { char nline[P_LINE];register i, j; register char *pn, *px, *py; for(pn = nline, i = 0; i <lmax+P_SPC; i++, pn++) *pn = ‘ ’; for (i = nc[ix], py = out[ix]; *py;py++, pn++) { if (*py == ‘ ’ || *py == ‘−’) *pn = ‘ ’; else { if (i%10== 0 || (i == 1 && nc[ix] != 1)) { j = (i < 0)? −i : i; for (px = pn; j;j/= 10, px−−) *px = j%10 + ‘0’; if (i < 0) *px = ‘−’; } else *pn = ‘ ’;i++; } } *pn = ‘\0’; nc[ix] = i; for (pn = nline; *pn; pn++) (void)putc(*pn, fx); (void) putc(‘\n’, fx); } /*  * put out a line (name,[num], seq. [num]): dumpblock()  */ static putline(ix) putline int   ix;{ ...putline int i; register char *px; for (px = namex[ix], i = 0; *px&& *px != ‘:’; px++, i++) (void) putc(*px, fx); for (;i < lmax+P_SPC;i++) (void) putc(‘ ’, fx); /* these count from 1:  * ni[] is currentelement (from 1)  * nc[] is number at start of current line  */ for (px= out[ix]; *px; px++) (void) putc(*px&0x7F, fx); (void) putc(‘\n’, fx);} /*  * put a line of stars (seqs always in out[0], out[1]): dumpblock() */ static stars() stars { int i; register char *p0, *p1, cx, *px; if(!*out[0] || (*out[0] == ‘ ’ && *(p0[0]) == ‘ ’) || !*out[1] || (*out[1]== ‘ ’ && *(po[1]) == ‘ ’)) return; px = star; for (i = lmax+P_SPC; i;i−−) *px++ = ‘ ’; for (p0 = out[0], p1 = out[1]; *p0 && *p1; p0++, p1++){ if (isalpha(*p0) && isalpha(*p1)) { if (xbm[*p0−‘A’]&xbm[*p1−‘A’]) {cx = ‘*’; nm++; } else if (!dna && _day[*p0− ‘A’][*p1−‘A’] > 0) cx =‘.’; else cx = ‘ ’; } else cx = ‘ ’; *px++ = cx; } *px++ = ‘\n’; *px =‘\0’; } /*  * strip path or prefix from pn, return len: pr_align()  */static stripname(pn) stripname char *pn; /* file name (may be path) */ {register char *px, *py; py = 0; for (px = pn; *px; px++) if (*px == ‘/’)py = px + 1; if (py) (void) strcpy(pn, py); return(strlen(pn)); } /*  *cleanup() -- cleanup any tmp file  * getseq() -- read in seq, set dna,len, maxlen  * g_calloc() -- calloc() with error checkin  * readjmps()-- get the good jmps, from tmp file if necessary  * writejmps() -- writea filled array of jmps to a tmp file: nw()  */ #include “nw.h” #include<sys/file.h> char *jname = “/tmp/homgXXXXXX”; /* tmp file for jmps */FILE *fj; int cleanup(); /* cleanup tmp file */ long lseek(); /*  *remove any tmp file if we blow  */ cleanup(i) cleanup int i; { if (fj)(void) unlink(jname); exit(i); } /*  * read, return ptr to seq, set dna,len, maxlen  * skip lines starting with ‘;’, ‘<’, or ‘>’  * seq in upperor lower case  */ char * getseq(file, len) getseq char *file; /* filename */ int *len; /* seq len */ { char line[1024], *pseq; register char*px, *py; int natgc, tlen; FILE *fp; if ((fp = fopen(file, “r”)) == 0) {fprintf(stderr, “%s: can't read %s\n”, prog, file); exit(1); } tlen =natgc = 0; while (fgets(line, 1024, fp)) { if (*line == ‘;’ || *line ==‘<’ || *line == ‘>’) continue; for (px = line; *px != ‘\n’; px++) if(isupper(*px) || islower(*px)) tlen++; } if ((pseq =malloc((unsigned)(tlen+6))) == 0) { fprintf(stderr, “%s: malloc() failedto get %d bytes for %s\n”, prog, tlen+6, file); exit(1); } pseq[0] =pseq[1] = pseq[2] = pseq[3] = ‘\0’; ...getseq py = pseq + 4; *len =tlen; rewind(fp); while (fgets(line, 1024, fp)) { if (*line == ‘;’ ||*line == ‘<’ || *line == ‘>’) continue; for (px = line; *px != ‘\n’;px++) { if (isupper(*px)) *py++ = *px; else if (islower(*px)) *py++ =toupper(*px); if (index(“ATGCU”, *(py−1))) natgc++; } } *py++ = ‘\0’;*py = ‘\0’; (void) fclose(fp); dna = natgc > (tlen/3); return(pseq+4); }char * g_calloc(msg, nx, sz) g_calloc char *msg; /* program, callingroutine */ int nx, sz; /* number and size of elements */ { char *px,*calloc(); if ((px = calloc((unsigned)nx, (unsigned)sz)) == 0) { if(*msg) { fprintf(stderr, “%s: g_calloc() failed %s (n= %d, sz= %d)\n”,prog, msg, nx, sz); exit(1); } } return(px); } /*  * get final jmps fromdx[] or tmp file, set pp[], reset dmax: main()  */ readjmps() readjmps {int fd = −1; int siz, i0, i1; register i, j, xx; if (fj) { (void)fclose(fj); if ((fd = open(jname, O_RDONLY, 0)) < 0) { fprintf(stderr,“%s: can't open() %s\n”, prog, jname); cleanup(1); } } for (i = i0 = i1= 0, dmax0 = dmax, xx = len0; ;i++) { while (1) { for (j =dx[dmax].ijmp; j >= 0 && dx[dmax].jp.x[j] >= xx; j−−) ; ...readjmps if(j < 0 && dx[dmax].offset && fj) { (void) lseek(fd, dx[dmax].offset, 0);(void) read(fd, (char *)&dx[dmax].jp, sizeof(struct jmp)); (void)read(fd, (char *)&dx[dmax].offset, sizeof(dx[dmax].offset));dx[dmax].ijmp = MAXJMP−1; } else break; } if (i >= JMPS) {fprintf(stderr, “%s: too many gaps in alignment\n”, prog); cleanup(1); }if (j >= 0) { siz = dx[dmax].jp.n[j]; xx = dx[dmax].jp.x[j]; dmax +=siz; if (siz < 0) { /* gap in second seq */ pp[1].n[il] = −siz; xx +=siz; /* id = xx − yy + len1 − 1  */ pp[1].x[il] = xx − dmax + len1 − 1;gapy++; ngapy −= siz; /* ignore MAXGAP when doing endgaps */ siz = (−siz< MAXGAP || endgaps)? −siz : MAXGAP; il++; } else if (siz > 0) { /* gapin first seq */ pp[0] .n[i0] = siz; pp[0] .x[i0] = xx; gapx++; ngapx +=siz; /* ignore MAXGAP when doing endgaps */ siz = (siz < MAXGAP ||endgaps)? siz : MAXGAP; i0++; } } else break; } /* reverse the order ofjmps  */ for (j = 0, i0−−; j < i0; j++, i0−−) { i = pp[0].n[j];pp[0].n[j] = pp[0].n[i0]; pp[0].n[i0] = i; i = pp[0].x[j]; pp[0].x[j] =pp[0].x[i0]; pp[0].x[i0] = i; } for (j = 0, i1−−; j < i1; j++, i1−−) { i= pp[1].n[j]; pp[1].n[j] = pp[1].n[i1]; pp[1].n[i1] = i; i = pp[1].x[j];pp[1].x[j] = pp[1].x[i1]; pp[1].x[i1] = i; } if (fd >= 0) (void)close(fd); if (fj) { (void) unlink(jname); fj = 0; offset = 0; } } /*  *write a filled jmp struct offset of the prev one (if any): nw()  */writejmps(ix) writejmps int ix; { char *mktemp(); if (!fj) { if(mktemp(jname) < 0) { fprintf(stderr, “%s: can't mktemp() %s\n”, prog,jname); cleanup(1); } if ((fj = fopen(jname, “w”)) == 0) {fprintf(stderr, “%s: can't write %s\n”, prog, jname); exit(1); } }(void) fwrite((char *)&dx[ix].jp, sizeof(struct jmp), 1, fj); (void)fwrite((char *)&dx[ix].offset, sizeof(dx[ix].offset), 1, fj); }

[0249] TABLE 2 PRO XXXXXXXXXXXXXXX (Length = 15 amino acids) ComparisonXXXXXYYYYYYY (Length = 12 amino acids) Protein

[0250] TABLE 3 PRO XXXXXXXXXX (Length = 10 amino acids) ComparisonXXXXXYYYYYYZZYZ (Length = 15 amino acids) Protein

[0251] TABLE 4 PRO-DNA NNNNNNNNNNNNNN (Length = 14 nucleotides)Comparison NNNNNNLLLLLLLLLL (Length = 16 nucleotides) DNA

[0252] TABLE 5 PRO-DNA NNNNNNNNNNNN (Length = 12 nucleotides) ComparisonDNA NNNNLLLVV (Length = 9 nucleotides) DNA

II. Compositions and Methods of the Invention A. Full-Length PROPolypeptides

[0253] The present invention provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in the presentapplication as PRO polypeptides. In particular, cDNAs encoding variousPRO polypeptides have been identified and isolated, as disclosed infurther detail in the Examples below. It is noted that proteins producedin separate expression rounds may be given different PRO numbers but theUNQ number is unique for any given DNA and the encoded protein, and willnot be changed. However, for sake of simplicity, in the presentspecification the protein encoded by the full length native nucleic acidmolecules disclosed herein as well as all further native homologues andvariants included in the foregoing definition of PRO, will be referredto as “PRO/number”, regardless of their origin or mode of preparation.

[0254] As disclosed in the Examples below, various cDNA clones have beendeposited with the ATCC. The actual nucleotide sequences of those clonescan readily be determined by the skilled artisan by sequencing of thedeposited clone using routine methods in the art. The predicted aminoacid sequence can be determined from the nucleotide sequence usingroutine skill. For the PRO polypeptides and encoding nucleic acidsdescribed herein, Applicants have identified what is believed to be thereading frame best identifiable with the sequence information availableat the time.

B. PRO Polypeptide Variants

[0255] In addition to the full-length native sequence PRO polypeptidesdescribed herein, it is contemplated that PRO variants can be prepared.PRO variants can be prepared by introducing appropriate nucleotidechanges into the PRO DNA, and/or by synthesis of the desired PROpolypeptide. Those skilled in the art will appreciate that amino acidchanges may alter post-translational processes of the PRO, such aschanging the number or position of glycosylation sites or altering themembrane anchoring characteristics.

[0256] Variations in the native full-length sequence PRO or in variousdomains of the PRO described herein, can be made, for example, using anyof the techniques and guidelines for conservative and non-conservativemutations set forth, for instance, in U.S. Pat. No. 5,364,934.Variations may be a substitution, deletion or insertion of one or morecodons encoding the PRO that results in a change in the amino acidsequence of the PRO as compared with the native sequence PRO. Optionallythe variation is by substitution of at least one amino acid with anyother amino acid in one or more of the domains of the PRO. Guidance indetermining which amino acid residue may be inserted, substituted ordeleted without adversely affecting the desired activity may be found bycomparing the sequence of the PRO with that of homologous known proteinmolecules and minimizing the number of amino acid sequence changes madein regions of high homology. Amino acid substitutions can be the resultof replacing one amino acid with another amino acid having similarstructural and/or chemical properties, such as the replacement of aleucine with a serine, i.e., conservative amino acid replacements.Insertions or deletions may optionally be in the range of about 1 to 5amino acids. The variation allowed may be determined by systematicallymaking insertions, deletions or substitutions of amino acids in thesequence and testing the resulting variants for activity exhibited bythe full-length or mature native sequence.

[0257] PRO polypeptide fragments are provided herein. Such fragments maybe truncated at the N-terminus or C-terminus, or may lack internalresidues, for example, when compared with a full length native protein.Certain fragments lack amino acid residues that are not essential for adesired biological activity of the PRO polypeptide.

[0258] PRO fragments may be prepared by any of a number of conventionaltechniques. Desired peptide fragments may be chemically synthesized. Analternative approach involves generating PRO fragments by enzymaticdigestion, e.g., by treating the protein with an enzyme known to cleaveproteins at sites defined by particular amino acid residues, or bydigesting the DNA with suitable restriction enzymes and isolating thedesired fragment. Yet another suitable technique involves isolating andamplifying a DNA fragment encoding a desired polypeptide fragment, bypolymerase chain reaction (PCR). Oligonucleotides that define thedesired termini of the DNA fragment are employed at the 5′ and 3′primers in the PCR. Preferably, PRO polypeptide fragments share at leastone biological and/or immunological activity with the native PROpolypeptide disclosed herein.

[0259] In particular embodiments, conservative substitutions of interestare shown in Table 6 under the heading of preferred substitutions. Ifsuch substitutions result in a change in biological activity, then moresubstantial changes, denominated exemplary substitutions in Table 6, oras further described below in reference to amino acid classes, areintroduced and the products screened. TABLE 6 Original ExemplaryPreferred Residue Substitutions Substitutions Ala (A) val; leu; ile valArg (R) lys; gln; asn lys Asn (N) gln; his; lys; arg gln Asp (D) glu gluCys (C) ser ser Gln (Q) asn asn Glu (E) asp asp Gly (G) pro; ala ala His(H) asn; gln; lys; arg arg Ile (I) leu; val; met; ala; phe; leunorleucine Leu (L) norleucine; ile; val; ile met; ala; phe Lys (K) arg;gln; asn arg Met (M) leu; phe; ile leu Phe (F) leu; val; ile; ala; tyrleu Pro (P) ala ala Ser (S) thr thr Thr (T) ser ser Trp (W) tyr; phe tyrTyr (Y) trp; phe; thr; ser phe Val (V) ile; leu; met; phe; leu ala;norleucine

[0260] Substantial modifications in function or immunological identityof the PRO polypeptide are accomplished by selecting substitutions thatdiffer significantly in their effect on maintaining (a) the structure ofthe polypeptide backbone in the area of the substitution, for example,as a sheet or helical conformation, (b) the charge or hydrophobicity ofthe molecule at the target site, or (c) the bulk of the side chain.Naturally occurring residues are divided into groups based on commonside-chain properties:

[0261] (1) hydrophobic: norleucine, met, ala, val, leu, ile;

[0262] (2) neutral hydrophilic: cys, ser, thr;

[0263] (3) acidic: asp, glu;

[0264] (4) basic: asn, gln, his, lys, arg;

[0265] (5) residues that influence chain orientation: gly, pro; and

[0266] (6) aromatic: trp, tyr, phe.

[0267] Non-conservative substitutions will entail exchanging a member ofone of these classes for another class. Such substituted residues alsomay be introduced into the conservative substitution sites or, morepreferably, into the remaining (non-conserved) sites.

[0268] The variations can be made using methods known in the art such asoligonucleotide-mediated (site-directed) mutagenesis, alanine scanning,and PCR mutagenesis. Site-directed mutagenesis [Carter et al., Nucl.Acids Res., 13:4331 (1986); Zoller et al., Nucl. Acids Res., 10:6487(1987)], cassette mutagenesis [Wells et al., Gene, 34:315 (1985)],restriction selection mutagenesis [Wells et al., Philos. Trans. R. Soc.London SerA, 317:415 (1986)] or other known techniques can be performedon the cloned DNA to produce the PRO variant DNA.

[0269] Scanning amino acid analysis can also be employed to identify oneor more amino acids along a contiguous sequence. Among the preferredscanning amino acids are relatively small, neutral amino acids. Suchamino acids include alanine, glycine, serine, and cysteine. Alanine istypically a preferred scanning amino acid among this group because iteliminates the side-chain beyond the beta-carbon and is less likely toalter the main-chain conformation of the variant [Cunningham and Wells,Science, 244: 1081-1085 (1989)]. Alanine is also typically preferredbecause it is the most common amino acid. Further, it is frequentlyfound in both buried and exposed positions [Creighton, The Proteins, (W.H. Freeman & Co., N.Y.); Chothia, J. Mol. Biol., 150:1 (1976)]. Ifalanine substitution does not yield adequate amounts of variant, anisoteric amino acid can be used.

C. Modifications of PRO

[0270] Covalent modifications of PRO are included within the scope ofthis invention. One type of covalent modification includes reactingtargeted amino acid residues of a PRO polypeptide with an organicderivatizing agent that is capable of reacting with selected side chainsor the N- or C-terminal residues of the PRO. Derivatization withbifunctional agents is useful, for instance, for crosslinking PRO to awater-insoluble support matrix or surface for use in the method forpurifying anti-PRO antibodies, and vice-versa. Commonly usedcrosslinking agents include, e.g., 1,1-bis (diazoacetyl)-2-phenylethane,glutaraldehyde, N-hydroxysuccinimide esters, for example, esters with4-azidosalicylic acid, homobifunctional imidoesters, includingdisuccinimidyl esters such as 3,3′-dithiobis(succinimidylpropionate),bifunctional maleimides such as bis-N-maleimido-1,8-octane and agentssuch as methyl-3-[(p-azidophenyl)dithio]propioimidate.

[0271] Other modifications include deamidation of glutaminyl andasparaginyl residues to the corresponding glutamyl and aspartylresidues, respectively, hydroxylation of proline and lysine,phosphorylation of hydroxyl groups of seryl or threonyl residues,methylation of the α-amino groups of lysine, arginine, and histidineside chains [T. E. Creighton, Proteins: Structure and MolecularProperties, W. H. Freeman & Co., San Francisco, pp. 79-86 (1983)],acetylation of the N-terminal amine, and amidation of any C-terminalcarboxyl group.

[0272] Another type of covalent modification of the PRO polypeptideincluded within the scope of this invention comprises altering thenative glycosylation pattern of the polypeptide. “Altering the nativeglycosylation pattern” is intended for purposes herein to mean deletingone or more carbohydrate moieties found in native sequence PRO (eitherby removing the underlying glycosylation site or by deleting theglycosylation by chemical and/or enzymatic means), and/or adding one ormore glycosylation sites that are not present in the native sequencePRO. In addition, the phrase includes qualitative changes in theglycosylation of the native proteins, involving a change in the natureand proportions of the various carbohydrate moieties present.

[0273] Addition of glycosylation sites to the PRO polypeptide may beaccomplished by altering the amino acid sequence. The alteration may bemade, for example, by the addition of, or substitution by, one or moreserine or threonine residues to the native sequence PRO (for O-linkedglycosylation sites). The PRO amino acid sequence may optionally bealtered through changes at the DNA level, particularly by mutating theDNA encoding the PRO polypeptide at preselected bases such that codonsare generated that will translate into the desired amino acids.

[0274] Another means of increasing the number of carbohydrate moietieson the PRO polypeptide is by chemical or enzymatic coupling ofglycosides to the polypeptide. Such methods are described in the art,e.g., in WO 87/05330 published Sep. 11, 1987, and in Aplin and Wriston,CRC Crit. Rev. Biochem., pp. 259-306 (1981).

[0275] Removal of carbohydrate moieties present on the PRO polypeptidemay be accomplished chemically or enzymatically or by mutationalsubstitution of codons encoding for amino acid residues that serve astargets for glycosylation. Chemical deglycosylation techniques are knownin the art and described, for instance, by Hakimuddin, et al., Arch.Biochem. Biophys., 259:52 (1987) and by Edge et al., Anal.

[0276] Biochem., 118:131 (1981). Enzymatic cleavage of carbohydratemoieties on polypeptides can be achieved by the use of a variety ofendo- and exo-glycosidases as described by Thotakura et al., Meth.Enzymol., 138:350 (1987).

[0277] Another type of covalent modification of PRO comprises linkingthe PRO polypeptide to one of a variety of nonproteinaceous polymers,e.g., polyethylene glycol (PEG), polypropylene glycol, orpolyoxyalkylenes, in the manner set forth in U.S. Pat. Nos. 4,640,835;4,496,689; 4,301,144; 4,670,417; 4,791,192 or 4,179,337.

[0278] The PRO of the present invention may also be modified in a way toform a chimeric molecule comprising PRO fused to another, heterologouspolypeptide or amino acid sequence.

[0279] In one embodiment, such a chimeric molecule comprises a fusion ofthe PRO with a tag polypeptide which provides an epitope to which ananti-tag antibody can selectively bind. The epitope tag is generallyplaced at the amino- or carboxyl-terminus of the PRO. The presence ofsuch epitope-tagged forms of the PRO can be detected using an antibodyagainst the tag polypeptide. Also, provision of the epitope tag enablesthe PRO to be readily purified by affinity purification using ananti-tag antibody or another type of affinity matrix that binds to theepitope tag. Various tag polypeptides and their respective antibodiesare well known in the art. Examples include poly-histidine (poly-his) orpoly-histidine-glycine (poly-his-gly) tags; the flu HA tag polypeptideand its antibody 12CA5 [Field et al., Mol. Cell. Biol., 8:2159-2165(1988)]; the c-myc tag and the 8F9, 3C7, 6E10, G4, B7 and 9E10antibodies thereto [Evan et al., Molecular and Cellular Biology,5:3610-3616 (1985)]; and the Herpes Simplex virus glycoprotein D (gD)tag and its antibody [Paborsky et al., Protein Engineering, 3(6):547-553(1990)]. Other tag polypeptides include the Flag-peptide [Hopp et al.,BioTechnology, 6:1204-1210 (1988)]; the KT3 epitope peptide [Martin etal., Science, 255:192-194 (1992)]; an α-tubulin epitope peptide [Skinneret al., J. Biol. Chem., 266:15163-15166 (1991)]; and the T7 gene 10protein peptide tag [Lutz-Freyermuth et al., Proc. Natl. Acad. Sci. USA,87:6393-6397 (1990)].

[0280] In an alternative embodiment, the chimeric molecule may comprisea fusion of the PRO with an immunoglobulin or a particular region of animmunoglobulin. For a bivalent form of the chimeric molecule (alsoreferred to as an “immunoadhesin”), such a fusion could be to the Fcregion of an IgG molecule. The Ig fusions preferably include thesubstitution of a soluble (transmembrane domain deleted or inactivated)form of a PRO polypeptide in place of at least one variable regionwithin an Ig molecule. In a particularly preferred embodiment, theimmunoglobulin fusion includes the hinge, CH2 and CH3, or the hinge,CH1, CH2 and CH3 regions of an IgG1 molecule. For the production ofimmunoglobulin fusions see also U.S. Pat. No. 5,428,130 issued Jun. 27,1995.

D. Preparation of PRO

[0281] The description below relates primarily to production of PRO byculturing cells transformed or transfected with a vector containing PROnucleic acid. It is, of course, contemplated that alternative methods,which are well known in the art, may be employed to prepare PRO. Forinstance, the PRO sequence, or portions thereof, may be produced bydirect peptide synthesis using solid-phase techniques [see, e.g.,Stewart et al., Solid-Phase Peptide Synthesis, W. H. Freeman Co., SanFrancisco, Calif. (1969); Merrifield, J. Am. Chem. Soc., 85:2149-2154(1963)]. In vitro protein synthesis may be performed using manualtechniques or by automation. Automated synthesis may be accomplished,for instance, using an Applied Biosystems Peptide Synthesizer (FosterCity, Calif.) using manufacturer's instructions. Various portions of thePRO may be chemically synthesized separately and combined using chemicalor enzymatic methods to produce the full-length PRO.

1. Isolation of DNA Encoding PRO

[0282] DNA encoding PRO may be obtained from a cDNA library preparedfrom tissue believed to possess the PRO mRNA and to express it at adetectable level. Accordingly, human PRO DNA can be convenientlyobtained from a cDNA library prepared from human tissue, such asdescribed in the Examples. The PRO-encoding gene may also be obtainedfrom a genomic library or by known synthetic procedures (e.g., automatednucleic acid synthesis).

[0283] Libraries can be screened with probes (such as antibodies to thePRO or oligonucleotides of at least about 20-80 bases) designed toidentify the gene of interest or the protein encoded by it. Screeningthe cDNA or genomic library with the selected probe may be conductedusing standard procedures, such as described in Sambrook et al.,Molecular Cloning: A Laboratory Manual (New York: Cold Spring HarborLaboratory Press, 1989). An alternative means to isolate the geneencoding PRO is to use PCR methodology [Sambrook et al., supra;Dieffenbach et al., PCR Primer: A Laboratory Manual (Cold Spring HarborLaboratory Press, 1995)].

[0284] The Examples below describe techniques for screening a cDNAlibrary. The oligonucleotide sequences selected as probes should be ofsufficient length and sufficiently unambiguous that false positives areminimized. The oligonucleotide is preferably labeled such that it can bedetected upon hybridization to DNA in the library being screened.Methods of labeling are well known in the art, and include the use ofradiolabels like ³²P-labeled ATP, biotinylation or enzyme labeling.Hybridization conditions, including moderate stringency and highstringency, are provided in Sambrook et al., supra.

[0285] Sequences identified in such library screening methods can becompared and aligned to other known sequences deposited and available inpublic databases such as GenBank or other private sequence databases.Sequence identity (at either the amino acid or nucleotide level) withindefined regions of the molecule or across the full-length sequence canbe determined using methods known in the art and as described herein.

[0286] Nucleic acid having protein coding sequence may be obtained byscreening selected cDNA or genomic libraries using the deduced aminoacid sequence disclosed herein for the first time, and, if necessary,using conventional primer extension procedures as described in Sambrooket al., supra, to detect precursors and processing intermediates of mRNAthat may not have been reverse-transcribed into cDNA.

2. Selection and Transformation of Host Cells

[0287] Host cells are transfected or transformed with expression orcloning vectors described herein for PRO production and cultured inconventional nutrient media modified as appropriate for inducingpromoters, selecting transformants, or amplifying the genes encoding thedesired sequences. The culture conditions, such as media, temperature,pH and the like, can be selected by the skilled artisan without undueexperimentation. In general, principles, protocols, and practicaltechniques for maximizing the productivity of cell cultures can be foundin Mammalian Cell Biotechnology: a Practical Approach, M. Butler, ed.(IRL Press, 1991) and Sambrook et al., supra.

[0288] Methods of eukaryotic cell transfection and prokaryotic celltransformation are known to the ordinarily skilled artisan, for example,CaCl₂, CaPO₄, liposome-mediated and electroporation. Depending on thehost cell used, transformation is performed using standard techniquesappropriate to such cells. The calcium treatment employing calciumchloride, as described in Sambrook et al., supra, or electroporation isgenerally used for prokaryotes. Infection with Agrobacterium tumefaciensis used for transformation of certain plant cells, as described by Shawet al., Gene, 23:315 (1983) and WO 89/05859 published Jun. 29, 1989. Formammalian cells without such cell walls, the calcium phosphateprecipitation method of Graham and van der Eb, Virology, 52:456-457(1978) can be employed. General aspects of mammalian cell host systemtransfections have been described in U.S. Pat. No. 4,399,216.Transformations into yeast are typically carried out according to themethod of Van Solingen et al., J. Bact., 130:946 (1977) and Hsiao etal., Proc. Natl. Acad. Sci. (USA), 76:3829 (1979). However, othermethods for introducing DNA into cells, such as by nuclearmicroinjection, electroporation, bacterial protoplast fusion with intactcells, or polycations, e.g., polybrene, polyornithine, may also be used.For various techniques for transforming mammalian cells, see Keown etal., Methods in Enzymology, 185:527-537 (1990) and Mansour et al.,Nature, 336:348-352 (1988).

[0289] Suitable host cells for cloning or expressing the DNA in thevectors herein include prokaryote, yeast, or higher eukaryote cells.Suitable prokaryotes include but are not limited to eubacteria, such asGram-negative or Gram-positive organisms, for example,Enterobacteriaceae such as E. coli. Various E. coli strains are publiclyavailable, such as E. coli K12 strain MM294 (ATCC 31,446); E. coli X1776(ATCC 31,537); E. coli strain W3110 (ATCC 27,325) and K5 772 (ATCC53,635). Other suitable prokaryotic host cells includeEnterobacteriaceae such as Escherichia, e.g., E. coli, Enterobacter,Erwinia, Klebsiella, Proteus, Salmonella, e.g., Salmonella typhimurium,Serratia, e.g., Serratia marcescans, and Shigella, as well as Bacillisuch as B. subtilis and B. licheniformis (e.g., B. licheniformis 41Pdisclosed in DD 266,710 published Apr. 12, 1989), Pseudomonas such as P.aeruginosa, and Streptomyces. These examples are illustrative ratherthan limiting. Strain W3110 is one particularly preferred host or parenthost because it is a common host strain for recombinant DNA productfermentations. Preferably, the host cell secretes minimal amounts ofproteolytic enzymes. For example, strain W3110 may be modified to effecta genetic mutation in the genes encoding proteins endogenous to thehost, with examples of such hosts including E. coli W3110 strain 1A2,which has the complete genotype tonA; E. coli W3110 strain 9E4, whichhas the complete genotype tonA ptr3; E. coli W3110 strain 27C7 (ATCC55,244), which has the complete genotype tonA ptr3 phoA E15(argF-lac)169 degP ompT kan^(r) ; E. coli W3110 strain 37D6, which hasthe complete genotype tonA ptr3 phoA E15 (argF-lac)169 degP ompT rbs7ilvG kan^(r) ; E. coli W3110 strain 40B4, which is strain 37D6 with anon-kanamycin resistant degP deletion mutation; and an E. coli strainhaving mutant periplasmic protease disclosed in U.S. Pat. No. 4,946,783issued Aug. 7, 1990. Alternatively, in vitro methods of cloning, e.g.,PCR or other nucleic acid polymerase reactions, are suitable.

[0290] In addition to prokaryotes, eukaryotic microbes such asfilamentous fungi or yeast are suitable cloning or expression hosts forPRO-encoding vectors. Saccharomyces cerevisiae is a commonly used lowereukaryotic host microorganism. Others include Schizosaccharomyces pombe(Beach and Nurse, Nature, 290: 140 [1981]; EP 139,383 published May 2,1985); Kluyveromyces hosts (U.S. Pat. No. 4,943,529; Fleer et al.,Bio/Technology, 9:968-975 (1991)) such as, e.g., K. lactis (MW98-8C,CBS683, CBS4574; Louvencourt et al., J. Bacteriol., 154(2):737-742[1983]), K. fragilis (ATCC 12,424), K. bulgaricus (ATCC 16,045), K.wickeramii (ATCC 24,178), K. waltii (ATCC 56,500), K. drosophilarum(ATCC 36,906; Van den Berg et al., Bio/Technology, 8:135 (1990)), K.thermotolerans, and K. marxianus; yarrowia (EP 402,226); Pichia pastoris(EP 183,070; Sreekrishna et al., J. Basic Microbiol., 28:265-278[1988]); Candida; Trichoderma reesia (EP 244,234); Neurospora crassa(Case et al., Proc. Natl. Acad. Sci. USA, 76:5259-5263 [1979]);Schwanniomyces such as Schwanniomyces occidentalis (EP 394,538 publishedOct. 31, 1990); and filamentous fungi such as, e.g., Neurospora,Penicillium, Tolypocladium (WO 91/000357 published Jan. 10, 1991), andAspergillus hosts such as A. nidulans (Ballance et al., Biochem.Biophys. Res. Commun., 112:284-289 [1983]; Tilburn et al., Gene,26:205-221 [1983]; Yelton et al., Proc. Natl. Acad. Sci. USA, 81:1470-1474 [1984]) and A. niger (Kelly and Hynes, EMBO J., 4:475-479[1985]). Methylotropic yeasts are suitable herein and include, but arenot limited to, yeast capable of growth on methanol selected from thegenera consisting of Hansenula, Candida, Kloeckera, Pichia,Saccharomyces, Torulopsis, and Rhodotorula. A list of specific speciesthat are exemplary of this class of yeasts may be found in C. Anthony,The Biochemistry of Methylotrophs, 269 (1982).

[0291] Suitable host cells for the expression of glycosylated PRO arederived from multicellular organisms. Examples of invertebrate cellsinclude insect cells such as Drosophila S2 and Spodoptera Sf9, as wellas plant cells. Examples of useful mammalian host cell lines includeChinese hamster ovary (CHO) and COS cells. More specific examplesinclude monkey kidney CV1 line transformed by SV40 (COS-7, ATCC CRL1651); human embryonic kidney line (293 or 293 cells subcloned forgrowth in suspension culture, Graham et al., J. Gen Virol., 36:59(1977)); Chinese hamster ovary cells/-DHFR (CHO, Urlaub and Chasin,Proc. Natl. Acad. Sci. USA, 77:4216 (1980)); mouse sertoli cells (TM4,Mather, Biol. Reprod., 23:243-251 (1980)); human lung cells (W138, ATCCCCL 75); human liver cells (Hep G2, HB 8065); and mouse mammary tumor(MMT 060562, ATCC CCL51). The selection of the appropriate host cell isdeemed to be within the skill in the art.

3. Selection and Use of a Replicable Vector

[0292] The nucleic acid (e.g., cDNA or genomic DNA) encoding PRO may beinserted into a replicable vector for cloning (amplification of the DNA)or for expression. Various vectors are publicly available. The vectormay, for example, be in the form of a plasmid, cosmid, viral particle,or phage. The appropriate nucleic acid sequence may be inserted into thevector by a variety of procedures. In general, DNA is inserted into anappropriate restriction endonuclease site(s) using techniques known inthe art. Vector components generally include, but are not limited to,one or more of a signal sequence, an origin of replication, one or moremarker genes, an enhancer element, a promoter, and a transcriptiontermination sequence. Construction of suitable vectors containing one ormore of these components employs standard ligation techniques which areknown to the skilled artisan.

[0293] The PRO may be produced recombinantly not only directly, but alsoas a fusion polypeptide with a heterologous polypeptide, which may be asignal sequence or other polypeptide having a specific cleavage site atthe N-terminus of the mature protein or polypeptide. In general, thesignal sequence may be a component of the vector, or it may be a part ofthe PRO-encoding DNA that is inserted into the vector. The signalsequence may be a prokaryotic signal sequence selected, for example,from the group of the alkaline phosphatase, penicillinase, lpp, orheat-stable enterotoxin II leaders. For yeast secretion the signalsequence may be, e.g., the yeast invertase leader, alpha factor leader(including Saccharomyces and Kluyveromyces α-factor leaders, the latterdescribed in U.S. Pat. No. 5,010,182), or acid phosphatase leader, theC. albicans glucoamylase leader (EP 362,179 published Apr. 4, 1990), orthe signal described in WO 90/13646 published Nov. 15, 1990. Inmammalian cell expression, mammalian signal sequences may be used todirect secretion of the protein, such as signal sequences from secretedpolypeptides of the same or related species, as well as viral secretoryleaders.

[0294] Both expression and cloning vectors contain a nucleic acidsequence that enables the vector to replicate in one or more selectedhost cells. Such sequences are well known for a variety of bacteria,yeast, and viruses. The origin of replication from the plasmid pBR322 issuitable for most Gram-negative bacteria, the 2μ plasmid origin issuitable for yeast, and various viral origins (SV40, polyoma,adenovirus, VSV or BPV) are useful for cloning vectors in mammaliancells.

[0295] Expression and cloning vectors will typically contain a selectiongene, also termed a selectable marker. Typical selection genes encodeproteins that (a) confer resistance to antibiotics or other toxins,e.g., ampicillin, neomycin, methotrexate, or tetracycline, (b)complement auxotrophic deficiencies, or (c) supply critical nutrientsnot available from complex media, e.g., the gene encoding D-alanineracemase for Bacilli.

[0296] An example of suitable selectable markers for mammalian cells arethose that enable the identification of cells competent to take up thePRO-encoding nucleic acid, such as DHFR or thymidine kinase. Anappropriate host cell when wild-type DHFR is employed is the CHO cellline deficient in DHFR activity, prepared and propagated as described byUrlaub et al., Proc. Natl. Acad. Sci. USA, 77:4216 (1980). A suitableselection gene for use in yeast is the trp 1 gene present in the yeastplasmid YRp7 [Stinchcomb et al., Nature, 282:39 (1979); Kingsman et al.,Gene, 7:141 (1979); Tschemper et al., Gene, 10:157 (1980)]. The trp 1gene provides a selection marker for a mutant strain of yeast lackingthe ability to grow in tryptophan, for example, ATCC No. 44076 or PEP4-1[Jones, Genetics, 85:12 (1977)].

[0297] Expression and cloning vectors usually contain a promoteroperably linked to the PRO-encoding nucleic acid sequence to direct mRNAsynthesis. Promoters recognized by a variety of potential host cells arewell known. Promoters suitable for use with prokaryotic hosts includethe β-lactamase and lactose promoter systems [Chang et al., Nature,275:615 (1978); Goeddel et al., Nature, 281:544 (1979)], alkalinephosphatase, a tryptophan (trp) promoter system [Goeddel, Nucleic AcidsRes., 8:4057 (1980); EP 36,776], and hybrid promoters such as the tacpromoter [deBoer et al., Proc. Natl. Acad. Sci. USA, 80:21-25 (1983)].Promoters for use in bacterial systems also will contain aShine-Dalgarno (S.D.) sequence operably linked to the DNA encoding PRO.

[0298] Examples of suitable promoting sequences for use with yeast hostsinclude the promoters for 3-phosphoglycerate kinase [Hitzeman et al., J.Biol. Chem., 255:2073 (1980)] or other glycolytic enzymes [Hess et al.,J. Adv. Enzyme Reg., 7:149 (1968); Holland, Biochemistry, 17:4900(1978)], such as enolase, glyceraldehyde-3-phosphate dehydrogenase,hexokinase, pyruvate decarboxylase, phosphofructokinase,glucose-6-phosphate isomerase, 3-phosphoglycerate mutase, pyruvatekinase, triosephosphate isomerase, phosphoglucose isomerase, andglucokinase.

[0299] Other yeast promoters, which are inducible promoters having theadditional advantage of transcription controlled by growth conditions,are the promoter regions for alcohol dehydrogenase 2, isocytochrome C,acid phosphatase, degradative enzymes associated with nitrogenmetabolism, metallothionein, glyceraldehyde-3-phosphate dehydrogenase,and enzymes responsible for maltose and galactose utilization. Suitablevectors and promoters for use in yeast expression are further describedin EP 73,657.

[0300] PRO transcription from vectors in mammalian host cells iscontrolled, for example, by promoters obtained from the genomes ofviruses such as polyoma virus, fowlpox virus (UK 2,211,504 publishedJul. 5, 1989), adenovirus (such as Adenovirus 2), bovine papillomavirus, avian sarcoma virus, cytomegalovirus, a retrovirus, hepatitis-Bvirus and Simian Virus 40 (SV40), from heterologous mammalian promoters,e.g., the actin promoter or an immunoglobulin promoter, and fromheat-shock promoters, provided such promoters are compatible with thehost cell systems.

[0301] Transcription of a DNA encoding the PRO by higher eukaryotes maybe increased by inserting an enhancer sequence into the vector.Enhancers are cis-acting elements of DNA, usually about from 10 to 300bp, that act on a promoter to increase its transcription. Many enhancersequences are now known from mammalian genes (globin, elastase, albumin,α-fetoprotein, and insulin). Typically, however, one will use anenhancer from a eukaryotic cell virus. Examples include the SV40enhancer on the late side of the replication origin (bp 100-270), thecytomegalovirus early promoter enhancer, the polyoma enhancer on thelate side of the replication origin, and adenovirus enhancers. Theenhancer may be spliced into the vector at a position 5′ or 3′ to thePRO coding sequence, but is preferably located at a site 5′ from thepromoter.

[0302] Expression vectors used in eukaryotic host cells (yeast, fungi,insect, plant, animal, human, or nucleated cells from othermulticellular organisms) will also contain sequences necessary for thetermination of transcription and for stabilizing the mRNA. Suchsequences are commonly available from the 5′ and, occasionally 3′,untranslated regions of eukaryotic or viral DNAs or cDNAs. These regionscontain nucleotide segments transcribed as polyadenylated fragments inthe untranslated portion of the mRNA encoding PRO.

[0303] Still other methods, vectors, and host cells suitable foradaptation to the synthesis of PRO in recombinant vertebrate cellculture are described in Gething et al., Nature, 293:620-625 (1981);Mantei et al., Nature, 281:40-46 (1979); EP 117,060; and EP 117,058.

4. Detecting Gene Amplification/Expression

[0304] Gene amplification and/or expression may be measured in a sampledirectly, for example, by conventional Southern blotting, Northernblotting to quantitate the transcription of mRNA [Thomas, Proc. Natl.Acad. Sci. USA, 77:5201(1980)], dot blotting (DNA analysis), or in situhybridization, using an appropriately labeled probe, based on thesequences provided herein. Alternatively, antibodies may be employedthat can recognize specific duplexes, including DNA duplexes, RNAduplexes, and DNA-RNA hybrid duplexes or DNA-protein duplexes. Theantibodies in turn may be labeled and the assay may be carried out wherethe duplex is bound to a surface, so that upon the formation of duplexon the surface, the presence of antibody bound to the duplex can bedetected.

[0305] Gene expression, alternatively, may be measured by immunologicalmethods, such as immunohistochemical staining of cells or tissuesections and assay of cell culture or body fluids, to quantitatedirectly the expression of gene product. Antibodies useful forimmunohistochemical staining and/or assay of sample fluids may be eithermonoclonal or polyclonal, and may be prepared in any mammal.Conveniently, the antibodies may be prepared against a native sequencePRO polypeptide or against a synthetic peptide based on the DNAsequences provided herein or against exogenous sequence fused to PRO DNAand encoding a specific antibody epitope.

5. Purification of Polypeptide

[0306] Forms of PRO may be recovered from culture medium or from hostcell lysates. If membrane-bound, it can be released from the membraneusing a suitable detergent solution (e.g. Triton-X 100) or by enzymaticcleavage. Cells employed in expression of PRO can be disrupted byvarious physical or chemical means, such as freeze-thaw cycling,sonication, mechanical disruption, or cell lysing agents.

[0307] It may be desired to purify PRO from recombinant cell proteins orpolypeptides. The following procedures are exemplary of suitablepurification procedures: by fractionation on an ion-exchange column;ethanol precipitation; reverse phase HPLC; chromatography on silica oron a cation-exchange resin such as DEAE; chromatofocusing; SDS-PAGE;ammonium sulfate precipitation; gel filtration using, for example,Sephadex G-75; protein A Sepharose columns to remove contaminants suchas IgG; and metal chelating columns to bind epitope-tagged forms of thePRO. Various methods of protein purification may be employed and suchmethods are known in the art and described for example in Deutscher,Methods in Enzymology, 182 (1990); Scopes, Protein Purification:Principles and Practice, Springer-Verlag, New York (1982). Thepurification step(s) selected will depend, for example, on the nature ofthe production process used and the particular PRO produced.

E. Uses for PRO

[0308] Nucleotide sequences (or their complement) encoding PRO havevarious applications in the art of molecular biology, including uses ashybridization probes, in chromosome and gene mapping and in thegeneration of anti-sense RNA and DNA. PRO nucleic acid will also beuseful for the preparation of PRO polypeptides by the recombinanttechniques described herein.

[0309] The full-length native sequence PRO gene, or portions thereof,may be used as hybridization probes for a cDNA library to isolate thefull-length PRO cDNA or to isolate still other cDNAs (for instance,those encoding naturally-occurring variants of PRO or PRO from otherspecies) which have a desired sequence identity to the native PROsequence disclosed herein. Optionally, the length of the probes will beabout 20 to about 50 bases. The hybridization probes may be derived fromat least partially novel regions of the full length native nucleotidesequence wherein those regions may be determined without undueexperimentation or from genomic sequences including promoters, enhancerelements and introns of native sequence PRO. By way of example, ascreening method will comprise isolating the coding region of the PROgene using the known DNA sequence to synthesize a selected probe ofabout 40 bases. Hybridization probes may be labeled by a variety oflabels, including radionucleotides such as ³²P or ³⁵S, or enzymaticlabels such as alkaline phosphatase coupled to the probe viaavidin/biotin coupling systems. Labeled probes having a sequencecomplementary to that of the PRO gene of the present invention can beused to screen libraries of human cDNA, genomic DNA or mRNA to determinewhich members of such libraries the probe hybridizes to. Hybridizationtechniques are described in further detail in the Examples below.

[0310] Any EST sequences disclosed in the present application maysimilarly be employed as probes, using the methods disclosed herein.

[0311] Other useful fragments of the PRO nucleic acids include antisenseor sense oligonucleotides comprising a singe-stranded nucleic acidsequence (either RNA or DNA) capable of binding to target PRO mRNA(sense) or PRO DNA (antisense) sequences. Antisense or senseoligonucleotides, according to the present invention, comprise afragment of the coding region of PRO DNA. Such a fragment generallycomprises at least about 14 nucleotides, preferably from about 14 to 30nucleotides. The ability to derive an antisense or a senseoligonucleotide, based upon a cDNA sequence encoding a given protein isdescribed in, for example, Stein and Cohen (Cancer Res. 48:2659, 1988)and van der Krol et al. (BioTechniques 6:958, 1988).

[0312] Binding of antisense or sense oligonucleotides to target nucleicacid sequences results in the formation of duplexes that blocktranscription or translation of the target sequence by one of severalmeans, including enhanced degradation of the duplexes, prematuretermination of transcription or translation, or by other means. Theantisense oligonucleotides thus may be used to block expression of PROproteins. Antisense or sense oligonucleotides further compriseoligonucleotides having modified sugar-phosphodiester backbones (orother sugar linkages, such as those described in WO 91/06629) andwherein such sugar linkages are resistant to endogenous nucleases. Sucholigonucleotides with resistant sugar linkages are stable in vivo (i.e.,capable of resisting enzymatic degradation) but retain sequencespecificity to be able to bind to target nucleotide sequences.

[0313] Other examples of sense or antisense oligonucleotides includethose oligonucleotides which are covalently linked to organic moieties,such as those described in WO 90/10048, and other moieties thatincreases affinity of the oligonucleotide for a target nucleic acidsequence, such as poly-(L-lysine). Further still, intercalating agents,such as ellipticine, and alkylating agents or metal may be attached tosense or antisense oligonucleotides to modify binding specificities ofthe antisense or sense oligonucleotide for the target nucleotidesequence.

[0314] Antisense or sense oligonucleotides may be introduced into a cellcontaining the target nucleic acid sequence by any gene transfer method,including, for example, CaPO₄-mediated DNA transfection,electroporation, or by using gene transfer vectors such as Epstein-Barrvirus. In a preferred procedure, an antisense or sense oligonucleotideis inserted into a suitable retroviral vector. A cell containing thetarget nucleic acid sequence is contacted with the recombinantretroviral vector, either in vivo or ex vivo. Suitable retroviralvectors include, but are not limited to, those derived from the murineretrovirus M-MuLV, N2 (a retrovirus derived from M-MuLV), or the doublecopy vectors designated DCT5A, DCT5B and DCT5C (see WO 90/13641).

[0315] Sense or antisense oligonucleotides also may be introduced into acell containing the target nucleotide sequence by formation of aconjugate with a ligand binding molecule, as described in WO 91/04753.Suitable ligand binding molecules include, but are not limited to, cellsurface receptors, growth factors, other cytokines, or other ligandsthat bind to cell surface receptors. Preferably, conjugation of theligand binding molecule does not substantially interfere with theability of the ligand binding molecule to bind to its correspondingmolecule or receptor, or block entry of the sense or antisenseoligonucleotide or its conjugated version into the cell.

[0316] Alternatively, a sense or an antisense oligonucleotide may beintroduced into a containing the target nucleic acid sequence byformation of an oligonucleotide-lipid complex, as described in WO90/10448. The sense or antisense oligonucleotide-lipid complex ispreferably dissociated within the cell by an endogenous lipase.

[0317] Antisense or sense RNA or DNA molecules are generally at leastabout 5 bases in length, about 10 bases in length, about 15 bases inlength, about 20 bases in length, about 25 bases in length, about 30bases in length, about 35 bases in length, about 40 bases in length,about 45 bases in length, about 50 bases in length, about 55 bases inlength, about 60 bases in length, about 65 bases in length, about 70bases in length, about 75 bases in length, about 80 bases in length,about 85 bases in length, about 90 bases in length, about 95 bases inlength, about 100 bases in length, or more.

[0318] The probes may also be employed in PCR techniques to generate apool of sequences for identification of closely related PRO codingsequences.

[0319] Nucleotide sequences encoding a PRO can also be used to constructhybridization probes for mapping the gene which encodes that PRO and forthe genetic analysis of individuals with genetic disorders. Thenucleotide sequences provided herein may be mapped to a chromosome andspecific regions of a chromosome using known techniques, such as in situhybridization, linkage analysis against known chromosomal markers, andhybridization screening with libraries.

[0320] When the coding sequences for PRO encode a protein which binds toanother protein (example, where the PRO is a receptor), the PRO can beused in assays to identify the other proteins or molecules involved inthe binding interaction. By such methods, inhibitors of thereceptor/ligand binding interaction can be identified. Proteins involvedin such binding interactions can also be used to screen for peptide orsmall molecule inhibitors or agonists of the binding interaction. Also,the receptor PRO can be used to isolate correlative ligand(s). Screeningassays can be designed to find lead compounds that mimic the biologicalactivity of a native PRO or a receptor for PRO. Such screening assayswill include assays amenable to high-throughput screening of chemicallibraries, making them particularly suitable for identifying smallmolecule drug candidates. Small molecules contemplated include syntheticorganic or inorganic compounds. The assays can be performed in a varietyof formats, including protein-protein binding assays, biochemicalscreening assays, immunoassays and cell based assays, which are wellcharacterized in the art.

[0321] Nucleic acids which encode PRO or its modified forms can also beused to generate either transgenic animals or “knock out” animals which,in turn, are useful in the development and screening of therapeuticallyuseful reagents. A transgenic animal (e.g., a mouse or rat) is an animalhaving cells that contain a transgene, which transgene was introducedinto the animal or an ancestor of the animal at a prenatal, e.g., anembryonic stage. A transgene is a DNA which is integrated into thegenome of a cell from which a transgenic animal develops. In oneembodiment, cDNA encoding PRO can be used to clone genomic DNA encodingPRO in accordance with established techniques and the genomic sequencesused to generate transgenic animals that contain cells which express DNAencoding PRO. Methods for generating transgenic animals, particularlyanimals such as mice or rats, have become conventional in the art andare described, for example, in U.S. Pat. Nos. 4,736,866 and 4,870,009.Typically, particular cells would be targeted for PRO transgeneincorporation with tissue-specific enhancers. Transgenic animals thatinclude a copy of a transgene encoding PRO introduced into the germ lineof the animal at an embryonic stage can be used to examine the effect ofincreased expression of DNA encoding PRO. Such animals can be used astester animals for reagents thought to confer protection from, forexample, pathological conditions associated with its overexpression. Inaccordance with this facet of the invention, an animal is treated withthe reagent and a reduced incidence of the pathological condition,compared to untreated animals bearing the transgene, would indicate apotential therapeutic intervention for the pathological condition.

[0322] Alternatively, non-human homologues of PRO can be used toconstruct a PRO “knock out” animal which has a defective or altered geneencoding PRO as a result of homologous recombination between theendogenous gene encoding PRO and altered genomic DNA encoding PROintroduced into an embryonic stem cell of the animal. For example, cDNAencoding PRO can be used to clone genomic DNA encoding PRO in accordancewith established techniques. A portion of the genomic DNA encoding PROcan be deleted or replaced with another gene, such as a gene encoding aselectable marker which can be used to monitor integration. Typically,several kilobases of unaltered flanking DNA (both at the 5′ and 3′ ends)are included in the vector [see e.g., Thomas and Capecchi, Cell, 51:503(1987) for a description of homologous recombination vectors]. Thevector is introduced into an embryonic stem cell line byelectroporation) and cells in which the introduced DNA has homologouslyrecombined with the endogenous DNA are selected [see e.g., Li et al.,Cell, 69:915 (1992)]. The selected cells are then injected into ablastocyst of an animal (e.g., a mouse or rat) to form aggregationchimeras [see e.g., Bradley, in Teratocarcinomas and Embryonic StemCells: A Practical Approach, E. J. Robertson, ed. (IRL, Oxford, 1987),pp. 113-152]. A chimeric embryo can then be implanted into a suitablepseudopregnant female foster animal and the embryo brought to term tocreate a “knock out” animal. Progeny harboring the homologouslyrecombined DNA in their germ cells can be identified by standardtechniques and used to breed animals in which all cells of the animalcontain the homologously recombined DNA. Knockout animals can becharacterized for instance, for their ability to defend against certainpathological conditions and for their development of pathologicalconditions due to absence of the PRO polypeptide.

[0323] Nucleic acid encoding the PRO polypeptides may also be used ingene therapy. In gene therapy applications, genes are introduced intocells in order to achieve in vivo synthesis of a therapeuticallyeffective genetic product, for example for replacement of a defectivegene. “Gene therapy” includes both conventional gene therapy where alasting effect is achieved by a single treatment, and the administrationof gene therapeutic agents, which involves the one time or repeatedadministration of a therapeutically effective DNA or mRNA. AntisenseRNAs and DNAs can be used as therapeutic agents for blocking theexpression of certain genes in vivo. It has already been shown thatshort antisense oligonucleotides can be imported into cells where theyact as inhibitors, despite their low intracellular concentrations causedby their restricted uptake by the cell membrane. (Zamecnik et al., Proc.Natl. Acad. Sci. USA 83:4143-4146 [1986]). The oligonucleotides can bemodified to enhance their uptake, e.g. by substituting their negativelycharged phosphodiester groups by uncharged groups.

[0324] There are a variety of techniques available for introducingnucleic acids into viable cells. The techniques vary depending uponwhether the nucleic acid is transferred into cultured cells in vitro, orin vivo in the cells of the intended host. Techniques suitable for thetransfer of nucleic acid into mammalian cells in vitro include the useof liposomes, electroporation, microinjection, cell fusion,DEAE-dextran, the calcium phosphate precipitation method, etc. Thecurrently preferred in vivo gene transfer techniques includetransfection with viral (typically retroviral) vectors and viral coatprotein-liposome mediated transfection (Dzau et al., Trends inBiotechnology 11, 205-210 [1993]). In some situations it is desirable toprovide the nucleic acid source with an agent that targets the targetcells, such as an antibody specific for a cell surface membrane proteinor the target cell, a ligand for a receptor on the target cell, etc.Where liposomes are employed, proteins which bind to a cell surfacemembrane protein associated with endocytosis may be used for targetingand/or to facilitate uptake, e.g. capsid proteins or fragments thereoftropic for a particular cell type, antibodies for proteins which undergointernalization in cycling, proteins that target intracellularlocalization and enhance intracellular half-life. The technique ofreceptor-mediated endocytosis is described, for example, by Wu et al.,J. Biol. Chem. 262, 4429-4432 (1987); and Wagner et al., Proc. Natl.Acad. Sci. USA 87, 3410-3414 (1990). For review of gene marking and genetherapy protocols see Anderson et al., Science 256, 808-813 (1992).

[0325] The PRO polypeptides described herein may also be employed asmolecular weight markers for protein electrophoresis purposes and theisolated nucleic acid sequences may be used for recombinantly expressingthose markers.

[0326] The nucleic acid molecules encoding the PRO polypeptides orfragments thereof described herein are useful for chromosomeidentification. In this regard, there exists an ongoing need to identifynew chromosome markers, since relatively few chromosome markingreagents, based upon actual sequence data are presently available. EachPRO nucleic acid molecule of the present invention can be used as achromosome marker.

[0327] The PRO polypeptides and nucleic acid molecules of the presentinvention may also be used diagnostically for tissue typing, wherein thePRO polypeptides of the present invention may be differentiallyexpressed in one tissue as compared to another, preferably in a diseasedtissue as compared to a normal tissue of the same tissue type. PROnucleic acid molecules will find use for generating probes for PCR,Northern analysis, Southern analysis and Western analysis.

[0328] The PRO polypeptides described herein may also be employed astherapeutic agents. The PRO polypeptides of the present invention can beformulated according to known methods to prepare pharmaceutically usefulcompositions, whereby the PRO product hereof is combined in admixturewith a pharmaceutically acceptable carrier vehicle. Therapeuticformulations are prepared for storage by mixing the active ingredienthaving the desired degree of purity with optional physiologicallyacceptable carriers, excipients or stabilizers (Remington'sPharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), in the formof lyophilized formulations or aqueous solutions. Acceptable carriers,excipients or stabilizers are nontoxic to recipients at the dosages andconcentrations employed, and include buffers such as phosphate, citrateand other organic acids; antioxidants including ascorbic acid; lowmolecular weight (less than about 10 residues) polypeptides; proteins,such as serum albumin, gelatin or immunoglobulins; hydrophilic polymerssuch as polyvinylpyrrolidone, amino acids such as glycine, glutamine,asparagine, arginine or lysine; monosaccharides, disaccharides and othercarbohydrates including glucose, mannose, or dextrins; chelating agentssuch as EDTA; sugar alcohols such as mannitol or sorbitol; salt-formingcounterions such as sodium; and/or nonionic surfactants such as TWEEN™,PLURONICS™ or PEG.

[0329] The formulations to be used for in vivo administration must besterile. This is readily accomplished by filtration through sterilefiltration membranes, prior to or following lyophilization andreconstitution.

[0330] Therapeutic compositions herein generally are placed into acontainer having a sterile access port, for example, an intravenoussolution bag or vial having a stopper pierceable by a hypodermicinjection needle.

[0331] The route of administration is in accord with known methods, e.g.injection or infusion by intravenous, intraperitoneal, intracerebral,intramuscular, intraocular, intraarterial or intralesional routes,topical administration, or by sustained release systems.

[0332] Dosages and desired drug concentrations of pharmaceuticalcompositions of the present invention may vary depending on theparticular use envisioned. The determination of the appropriate dosageor route of administration is well within the skill of an ordinaryphysician. Animal experiments provide reliable guidance for thedetermination of effective doses for human therapy. Interspecies scalingof effective doses can be performed following the principles laid downby Mordenti, J. and Chappell, W. “The use of interspecies scaling intoxicokinetics” In Toxicokinetics and New Drug Development, Yacobi etal., Eds., Pergamon Press, New York 1989, pp. 42-96.

[0333] When in vivo administration of a PRO polypeptide or agonist orantagonist thereof is employed, normal dosage amounts may vary fromabout 10 ng/kg to up to 100 mg/kg of mammal body weight or more per day,preferably about 1 μg/kg/day to 10 mg/kg/day, depending upon the routeof administration. Guidance as to particular dosages and methods ofdelivery is provided in the literature; see, for example, U.S. Pat. Nos.4,657,760; 5,206,344; or 5,225,212. It is anticipated that differentformulations will be effective for different treatment compounds anddifferent disorders, that administration targeting one organ or tissue,for example, may necessitate delivery in a manner different from that toanother organ or tissue.

[0334] Where sustained-release administration of a PRO polypeptide isdesired in a formulation with release characteristics suitable for thetreatment of any disease or disorder requiring administration of the PROpolypeptide, microencapsulation of the PRO polypeptide is contemplated.Microencapsulation of recombinant proteins for sustained release hasbeen successfully performed with human growth hormone (rhGH),interferon- (rhIFN-), interleukin-2, and MN rgp120. Johnson et al., Nat.Med., 2:795-799 (1996); Yasuda, Biomed. Ther., 27:1221-1223 (1993); Horaet al., Bio/Technology, 8:755-758 (1990); Cleland, “Design andProduction of Single Immunization Vaccines Using PolylactidePolyglycolide Microsphere Systems,” in Vaccine Design: The Subunit andAdjuvant Approach, Powell and Newman, eds, (Plenum Press: New York,1995), pp. 439-462; WO 97/03692, WO 96/40072, WO 96/07399; and U.S. Pat.No. 5,654,010.

[0335] The sustained-release formulations of these proteins weredeveloped using polylactic-coglycolic acid (PLGA) polymer due to itsbiocompatibility and wide range of biodegradable properties. Thedegradation products of PLGA, lactic and glycolic acids, can be clearedquickly within the human body. Moreover, the degradability of thispolymer can be adjusted from months to years depending on its molecularweight and composition. Lewis, “Controlled release of bioactive agentsfrom lactide/glycolide polymer,” in: M. Chasin and R. Langer (Eds.),Biodegradable Polymers as Drug Delivery Systems (Marcel Dekker: NewYork, 1990), pp.1-41.

[0336] This invention encompasses methods of screening compounds toidentify those that mimic the PRO polypeptide (agonists) or prevent theeffect of the PRO polypeptide (antagonists). Screening assays forantagonist drug candidates are designed to identify compounds that bindor complex with the PRO polypeptides encoded by the genes identifiedherein, or otherwise interfere with the interaction of the encodedpolypeptides with other cellular proteins. Such screening assays willinclude assays amenable to high-throughput screening of chemicallibraries, making them particularly suitable for identifying smallmolecule drug candidates.

[0337] The assays can be performed in a variety of formats, includingprotein-protein binding assays, biochemical screening assays,immunoassays, and cell-based assays, which are well characterized in theart.

[0338] All assays for antagonists are common in that they call forcontacting the drug candidate with a PRO polypeptide encoded by anucleic acid identified herein under conditions and for a timesufficient to allow these two components to interact.

[0339] In binding assays, the interaction is binding and the complexformed can be isolated or detected in the reaction mixture. In aparticular embodiment, the PRO polypeptide encoded by the geneidentified herein or the drug candidate is immobilized on a solid phase,e.g., on a microtiter plate, by covalent or non-covalent attachments.Non-covalent attachment generally is accomplished by coating the solidsurface with a solution of the PRO polypeptide and drying.Alternatively, an immobilized antibody, e.g., a monoclonal antibody,specific for the PRO polypeptide to be immobilized can be used to anchorit to a solid surface. The assay is performed by adding thenon-immobilized component, which may be labeled by a detectable label,to the immobilized component, e.g., the coated surface containing theanchored component. When the reaction is complete, the non-reactedcomponents are removed, e.g., by washing, and complexes anchored on thesolid surface are detected. When the originally non-immobilizedcomponent carries a detectable label, the detection of label immobilizedon the surface indicates that complexing occurred. Where the originallynon-immobilized component does not carry a label, complexing can bedetected, for example, by using a labeled antibody specifically bindingthe immobilized complex.

[0340] If the candidate compound interacts with but does not bind to aparticular PRO polypeptide encoded by a gene identified herein, itsinteraction with that polypeptide can be assayed by methods well knownfor detecting protein-protein interactions. Such assays includetraditional approaches, such as, e.g., cross-linking,co-immunoprecipitation, and co-purification through gradients orchromatographic columns. In addition, protein-protein interactions canbe monitored by using a yeast-based genetic system described by Fieldsand co-workers (Fields and Song, Nature (London), 340:245-246 (1989);Chien et al., Proc. Natl. Acad. Sci. USA, 88:9578-9582 (1991)) asdisclosed by Chevray and Nathans, Proc. Natl. Acad. Sci. USA, 89:5789-5793 (1991). Many transcriptional activators, such as yeast GAL4,consist of two physically discrete modular domains, one acting as theDNA-binding domain, the other one functioning as thetranscription-activation domain. The yeast expression system describedin the foregoing publications (generally referred to as the “two-hybridsystem”) takes advantage of this property, and employs two hybridproteins, one in which the target protein is fused to the DNA-bindingdomain of GAL4, and another, in which candidate activating proteins arefused to the activation domain. The expression of a GAL1-lacZ reportergene under control of a GAL4-activated promoter depends onreconstitution of GAL4 activity via protein-protein interaction.Colonies containing interacting polypeptides are detected with achromogenic substrate for β-galactosidase. A complete kit (MATCHMAKER™)for identifying protein-protein interactions between two specificproteins using the two-hybrid technique is commercially available fromClontech. This system can also be extended to map protein domainsinvolved in specific protein interactions as well as to pinpoint aminoacid residues that are crucial for these interactions.

[0341] Compounds that interfere with the interaction of a gene encodinga PRO polypeptide identified herein and other intra- or extracellularcomponents can be tested as follows: usually a reaction mixture isprepared containing the product of the gene and the intra- orextracellular component under conditions and for a time allowing for theinteraction and binding of the two products. To test the ability of acandidate compound to inhibit binding, the reaction is run in theabsence and in the presence of the test compound. In addition, a placebomay be added to a third reaction mixture, to serve as positive control.The binding (complex formation) between the test compound and the intra-or extracellular component present in the mixture is monitored asdescribed hereinabove. The formation of a complex in the controlreaction(s) but not in the reaction mixture containing the test compoundindicates that the test compound interferes with the interaction of thetest compound and its reaction partner.

[0342] To assay for antagonists, the PRO polypeptide may be added to acell along with the compound to be screened for a particular activityand the ability of the compound to inhibit the activity of interest inthe presence of the PRO polypeptide indicates that the compound is anantagonist to the PRO polypeptide. Alternatively, antagonists may bedetected by combining the PRO polypeptide and a potential antagonistwith membrane-bound PRO polypeptide receptors or recombinant receptorsunder appropriate conditions for a competitive inhibition assay. The PROpolypeptide can be labeled, such as by radioactivity, such that thenumber of PRO polypeptide molecules bound to the receptor can be used todetermine the effectiveness of the potential antagonist. The geneencoding the receptor can be identified by numerous methods known tothose of skill in the art, for example, ligand panning and FACS sorting.Coligan et al., Current Protocols in Immun., 1(2): Chapter 5 (1991).Preferably, expression cloning is employed wherein polyadenylated RNA isprepared from a cell responsive to the PRO polypeptide and a cDNAlibrary created from this RNA is divided into pools and used totransfect COS cells or other cells that are not responsive to the PROpolypeptide. Transfected cells that are grown on glass slides areexposed to labeled PRO polypeptide. The PRO polypeptide can be labeledby a variety of means including iodination or inclusion of a recognitionsite for a site-specific protein kinase. Following fixation andincubation, the slides are subjected to autoradiographic analysis.Positive pools are identified and sub-pools are prepared andre-transfected using an interactive sub-pooling and re-screeningprocess, eventually yielding a single clone that encodes the putativereceptor.

[0343] As an alternative approach for receptor identification, labeledPRO polypeptide can be photoaffinity-linked with cell membrane orextract preparations that express the receptor molecule. Cross-linkedmaterial is resolved by PAGE and exposed to X-ray film. The labeledcomplex containing the receptor can be excised, resolved into peptidefragments, and subjected to protein micro-sequencing. The amino acidsequence obtained from micro-sequencing would be used to design a set ofdegenerate oligonucleotide probes to screen a cDNA library to identifythe gene encoding the putative receptor.

[0344] In another assay for antagonists, mammalian cells or a membranepreparation expressing the receptor would be incubated with labeled PROpolypeptide in the presence of the candidate compound. The ability ofthe compound to enhance or block this interaction could then bemeasured.

[0345] More specific examples of potential antagonists include anoligonucleotide that binds to the fusions of immunoglobulin with PROpolypeptide, and, in particular, antibodies including, withoutlimitation, poly- and monoclonal antibodies and antibody fragments,single-chain antibodies, anti-idiotypic antibodies, and chimeric orhumanized versions of such antibodies or fragments, as well as humanantibodies and antibody fragments. Alternatively, a potential antagonistmay be a closely related protein, for example, a mutated form of the PROpolypeptide that recognizes the receptor but imparts no effect, therebycompetitively inhibiting the action of the PRO polypeptide.

[0346] Another potential PRO polypeptide antagonist is an antisense RNAor DNA construct prepared using antisense technology, where, e.g., anantisense RNA or DNA molecule acts to block directly the translation ofmRNA by hybridizing to targeted mRNA and preventing protein translation.Antisense technology can be used to gene expression through triple-helixformation or antisense DNA or RNA, both of which methods are based onbinding of a polynucleotide to DNA or RNA. For example, the 5′ codingportion of the polynucleotide sequence, which encodes the mature PROpolypeptides herein, is used to design an antisense RNA oligonucleotideof from about 10 to 40 base pairs in length. A DNA oligonucleotide isdesigned to be complementary to a region of the gene involved intranscription (triple helix—see Lee et al., Nucl. Acids Res., 6:3073(1979); Cooney et al., Science, 241: 456 (1988); Dervan et al., Science,251:1360 (1991)), thereby preventing transcription and the production ofthe PRO polypeptide. The antisense RNA oligonucleotide hybridizes to themRNA in vivo and blocks translation of the mRNA molecule into the PROpolypeptide (antisense—Okano, Neurochem., 56:560 (1991);Oligodeoxynucleotides as Antisense Inhibitors of Gene Expression (CRCPress: Boca Raton, Fla., 1988). The oligonucleotides described above canalso be delivered to cells such that the antisense RNA or DNA may beexpressed in vivo to inhibit production of the PRO polypeptide. Whenantisense DNA is used, oligodeoxyribonucleotides derived from thetranslation-initiation site, e.g., between about −10 and +10 positionsof the target gene nucleotide sequence, are preferred.

[0347] Potential antagonists include small molecules that bind to theactive site, the receptor binding site, or growth factor or otherrelevant binding site of the PRO polypeptide, thereby blocking thenormal biological activity of the PRO polypeptide. Examples of smallmolecules include, but are not limited to, small peptides orpeptide-like molecules, preferably soluble peptides, and syntheticnon-peptidyl organic or inorganic compounds.

[0348] Ribozymes are enzymatic RNA molecules capable of catalyzing thespecific cleavage of RNA. Ribozymes act by sequence-specifichybridization to the complementary target RNA, followed byendonucleolytic cleavage. Specific ribozyme cleavage sites within apotential RNA target can be identified by known techniques. For furtherdetails see, e.g., Rossi, Current Biology, 4:469-471 (1994), and PCTpublication No. WO 97/33551 (published Sep. 18, 1997).

[0349] Nucleic acid molecules in triple-helix formation used to inhibittranscription should be single-stranded and composed ofdeoxynucleotides. The base composition of these oligonucleotides isdesigned such that it promotes triple-helix formation via Hoogsteenbase-pairing rules, which generally require sizeable stretches ofpurines or pyrimidines on one strand of a duplex. For further detailssee, e.g., PCT publication No. WO 97/33551, supra.

[0350] These small molecules can be identified by any one or more of thescreening assays discussed hereinabove and/or by any other screeningtechniques well known for those skilled in the art.

[0351] Diagnostic and therapeutic uses of the herein disclosed moleculesmay also be based upon the positive functional assay hits disclosed anddescribed below.

F. Anti-PRO Antibodies

[0352] The present invention further provides anti-PRO antibodies.Exemplary antibodies include polyclonal, monoclonal, humanized,bispecific, and heteroconjugate antibodies.

1. Polyclonal Antibodies

[0353] The anti-PRO antibodies may comprise polyclonal antibodies.Methods of preparing polyclonal antibodies are known to the skilledartisan. Polyclonal antibodies can be raised in a mammal, for example,by one or more injections of an immunizing agent and, if desired, anadjuvant. Typically, the immunizing agent and/or adjuvant will beinjected in the mammal by multiple subcutaneous or intraperitonealinjections. The immunizing agent may include the PRO polypeptide or afusion protein thereof. It may be useful to conjugate the immunizingagent to a protein known to be immunogenic in the mammal beingimmunized. Examples of such immunogenic proteins include but are notlimited to keyhole limpet hemocyanin, serum albumin, bovinethyroglobulin, and soybean trypsin inhibitor. Examples of adjuvantswhich may be employed include Freund's complete adjuvant and MPL-TDMadjuvant (monophosphoryl Lipid A, synthetic trehalose dicorynomycolate).The immunization protocol may be selected by one skilled in the artwithout undue experimentation.

2. Monoclonal Antibodies

[0354] The anti-PRO antibodies may, alternatively, be monoclonalantibodies. Monoclonal antibodies may be prepared using hybridomamethods, such as those described by Kohler and Milstein, Nature, 256:495(1975). In a hybridoma method, a mouse, hamster, or other appropriatehost animal, is typically immunized with an immunizing agent to elicitlymphocytes that produce or are capable of producing antibodies thatwill specifically bind to the immunizing agent. Alternatively, thelymphocytes may be immunized in vitro.

[0355] The immunizing agent will typically include the PRO polypeptideor a fusion protein thereof. Generally, either peripheral bloodlymphocytes (“PBLs”) are used if cells of human origin are desired, orspleen cells or lymph node cells are used if non-human mammalian sourcesare desired. The lymphocytes are then fused with an immortalized cellline using a suitable fusing agent, such as polyethylene glycol, to forma hybridoma cell [Goding, Monoclonal Antibodies: Principles andPractice, Academic Press, (1986) pp. 59-103]. Immortalized cell linesare usually transformed mammalian cells, particularly myeloma cells ofrodent, bovine and human origin. Usually, rat or mouse myeloma celllines are employed. The hybridoma cells may be cultured in a suitableculture medium that preferably contains one or more substances thatinhibit the growth or survival of the unfused, immortalized cells. Forexample, if the parental cells lack the enzyme hypoxanthine guaninephosphoribosyl transferase (HGPRT or HPRT), the culture medium for thehybridomas typically will include hypoxanthine, aminopterin, andthymidine (“HAT medium”), which substances prevent the growth ofHGPRT-deficient cells.

[0356] Preferred immortalized cell lines are those that fuseefficiently, support stable high level expression of antibody by theselected antibody-producing cells, and are sensitive to a medium such asHAT medium. More preferred immortalized cell lines are murine myelomalines, which can be obtained, for instance, from the Salk Institute CellDistribution Center, San Diego, Calif. and the American Type CultureCollection, Manassas, Va. Human myeloma and mouse-human heteromyelomacell lines also have been described for the production of humanmonoclonal antibodies [Kozbor, J. Immunol., 133:3001 (1984); Brodeur etal., Monoclonal Antibody Production Techniques and Applications, MarcelDekker, Inc., New York, (1987) pp. 51-63].

[0357] The culture medium in which the hybridoma cells are cultured canthen be assayed for the presence of monoclonal antibodies directedagainst PRO. Preferably, the binding specificity of monoclonalantibodies produced by the hybridoma cells is determined byimmunoprecipitation or by an in vitro binding assay, such asradioimmunoassay (RIA) or enzyme-linked immunoabsorbent assay (ELISA).Such techniques and assays are known in the art. The binding affinity ofthe monoclonal antibody can, for example, be determined by the Scatchardanalysis of Munson and Pollard, Anal. Biochem., 107:220 (1980).

[0358] After the desired hybridoma cells are identified, the clones maybe subcloned by limiting dilution procedures and grown by standardmethods [Goding, supra]. Suitable culture media for this purposeinclude, for example, Dulbecco's Modified Eagle's Medium and RPMI-1640medium. Alternatively, the hybridoma cells may be grown in vivo asascites in a mammal.

[0359] The monoclonal antibodies secreted by the subclones may beisolated or purified from the culture medium or ascites fluid byconventional immunoglobulin purification procedures such as, forexample, protein A-Sepharose, hydroxylapatite chromatography, gelelectrophoresis, dialysis, or affinity chromatography.

[0360] The monoclonal antibodies may also be made by recombinant DNAmethods, such as those described in U.S. Pat. No. 4,816,567. DNAencoding the monoclonal antibodies of the invention can be readilyisolated and sequenced using conventional procedures (e.g., by usingoligonucleotide probes that are capable of binding specifically to genesencoding the heavy and light chains of murine antibodies). The hybridomacells of the invention serve as a preferred source of such DNA. Onceisolated, the DNA may be placed into expression vectors, which are thentransfected into host cells such as simian COS cells, Chinese hamsterovary (CHO) cells, or myeloma cells that do not otherwise produceimmunoglobulin protein, to obtain the synthesis of monoclonal antibodiesin the recombinant host cells. The DNA also may be modified, forexample, by substituting the coding sequence for human heavy and lightchain constant domains in place of the homologous murine sequences [U.S.Pat. No. 4,816,567; Morrison et al., supra] or by covalently joining tothe immunoglobulin coding sequence all or part of the coding sequencefor a non-immunoglobulin polypeptide. Such a non-immunoglobulinpolypeptide can be substituted for the constant domains of an antibodyof the invention, or can be substituted for the variable domains of oneantigen-combining site of an antibody of the invention to create achimeric bivalent antibody.

[0361] The antibodies may be monovalent antibodies. Methods forpreparing monovalent antibodies are well known in the art. For example,one method involves recombinant expression of immunoglobulin light chainand modified heavy chain. The heavy chain is truncated generally at anypoint in the Fc region so as to prevent heavy chain crosslinking.Alternatively, the relevant cysteine residues are substituted withanother amino acid residue or are deleted so as to prevent crosslinking.

[0362] In vitro methods are also suitable for preparing monovalentantibodies. Digestion of antibodies to produce fragments thereof,particularly, Fab fragments, can be accomplished using routinetechniques known in the art.

3. Human and Humanized Antibodies

[0363] The anti-PRO antibodies of the invention may further comprisehumanized antibodies or human antibodies. Humanized forms of non-human(e.g., murine) antibodies are chimeric immunoglobulins, immunoglobulinchains or fragments thereof (such as Fv, Fab, Fab′, F(ab′)₂ or otherantigen-binding subsequences of antibodies) which contain minimalsequence derived from non-human immunoglobulin. Humanized antibodiesinclude human immunoglobulins (recipient antibody) in which residuesfrom a complementary determining region (CDR) of the recipient arereplaced by residues from a CDR of a non-human species (donor antibody)such as mouse, rat or rabbit having the desired specificity, affinityand capacity. In some instances, Fv framework residues of the humanimmunoglobulin are replaced by corresponding non-human residues.Humanized antibodies may also comprise residues which are found neitherin the recipient antibody nor in the imported CDR or frameworksequences. In general, the humanized antibody will comprisesubstantially all of at least one, and typically two, variable domains,in which all or substantially all of the CDR regions correspond to thoseof a non-human immunoglobulin and all or substantially all of the FRregions are those of a human immunoglobulin consensus sequence. Thehumanized antibody optimally also will comprise at least a portion of animmunoglobulin constant region (Fc), typically that of a humanimmunoglobulin [Jones et al., Nature, 321:522-525 (1986); Riechmann etal., Nature, 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol.,2:593-596 (1992)].

[0364] Methods for humanizing non-human antibodies are well known in theart. Generally, a humanized antibody has one or more amino acid residuesintroduced into it from a source which is non-human. These non-humanamino acid residues are often referred to as “import” residues, whichare typically taken from an “import” variable domain. Humanization canbe essentially performed following the method of Winter and co-workers[Jones et al., Nature, 321:522-525 (1986); Riechmann et al., Nature,332:323-327 (1988); Verhoeyen et al., Science, 239:1534-1536 (1988)], bysubstituting rodent CDRs or CDR sequences for the correspondingsequences of a human antibody. Accordingly, such “humanized” antibodiesare chimeric antibodies (U.S. Pat. No. 4,816,567), wherein substantiallyless than an intact human variable domain has been substituted by thecorresponding sequence from a non-human species. In practice, humanizedantibodies are typically human antibodies in which some CDR residues andpossibly some FR residues are substituted by residues from analogoussites in rodent antibodies.

[0365] Human antibodies can also be produced using various techniquesknown in the art, including phage display libraries [Hoogenboom andWinter, J. Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol.,222:581 (1991)]. The techniques of Cole et al. and Boerner et al. arealso available for the preparation of human monoclonal antibodies (Coleet al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77(1985) and Boerner et al., J. Immunol., 147(1):86-95 (1991)]. Similarly,human antibodies can be made by introducing of human immunoglobulin lociinto transgenic animals, e.g., mice in which the endogenousimmunoglobulin genes have been partially or completely inactivated. Uponchallenge, human antibody production is observed, which closelyresembles that seen in humans in all respects, including generearrangement, assembly, and antibody repertoire. This approach isdescribed, for example, in U.S. Pat. Nos. 5,545,807; 5,545,806;5,569,825; 5,625,126; 5,633,425; 5,661,016, and in the followingscientific publications: Marks et al., Bio/Technology 10, 779-783(1992); Lonberg et al., Nature 368 856-859 (1994); Morrison, Nature 368,812-13 (1994); Fishwild et al., Nature Biotechnology 14, 845-51 (1996);Neuberger, Nature Biotechnology 14, 826 (1996); Lonberg and Huszar,Intern. Rev. Immunol. 13 65-93 (1995).

[0366] The antibodies may also be affinity matured using known selectionand/or mutagenesis methods as described above. Preferred affinitymatured antibodies have an affinity which is five times, more preferably10 times, even more preferably 20 or 30 times greater than the startingantibody (generally murine, humanized or human) from which the maturedantibody is prepared.

4. Bispecific Antibodies

[0367] Bispecific antibodies are monoclonal, preferably human orhumanized, antibodies that have binding specificities for at least twodifferent antigens. In the present case, one of the bindingspecificities is for the PRO, the other one is for any other antigen,and preferably for a cell-surface protein or receptor or receptorsubunit.

[0368] Methods for making bispecific antibodies are known in the art.Traditionally, the recombinant production of bispecific antibodies isbased on the co-expression of two immunoglobulin heavy-chain/light-chainpairs, where the two heavy chains have different specificities [Milsteinand Cuello, Nature, 305:537-539 (1983)]. Because of the randomassortment of immunoglobulin heavy and light chains, these hybridomas(quadromas) produce a potential mixture of ten different antibodymolecules, of which only one has the correct bispecific structure. Thepurification of the correct molecule is usually accomplished by affinitychromatography steps. Similar procedures are disclosed in WO 93/08829,published May 13, 1993, and in Traunecker et al., EMBO J., 10:3655-3659(1991).

[0369] Antibody variable domains with the desired binding specificities(antibody-antigen combining sites) can be fused to immunoglobulinconstant domain sequences. The fusion preferably is with animmunoglobulin heavy-chain constant domain, comprising at least part ofthe hinge, CH2, and CH3 regions. It is preferred to have firstheavy-chain constant region (CH1) containing the site necessary forlight-chain binding present in at least one of the fusions. DNAsencoding the immunoglobulin heavy-chain fusions and, if desired, theimmunoglobulin light chain, are inserted into separate expressionvectors, and are co-transfected into a suitable host organism. Forfurther details of generating bispecific antibodies see, for example,Suresh et al., Methods in Enzymology, 121:210 (1986).

[0370] According to another approach described in WO 96/27011, theinterface between a pair of antibody molecules can be engineered tomaximize the percentage of heterodimers which are recovered fromrecombinant cell culture. The preferred interface comprises at least apart of the CH3 region of an antibody constant domain. In this method,one or more small amino acid side chains from the interface of the firstantibody molecule are replaced with larger side chains (e.g. tyrosine ortryptophan). Compensatory “cavities” of identical or similar size to thelarge side chain(s) are created on the interface of the second antibodymolecule by replacing large amino acid side chains with smaller ones(e.g. alanine or threonine). This provides a mechanism for increasingthe yield of the heterodimer over other unwanted end-products such ashomodimers.

[0371] Bispecific antibodies can be prepared as full length antibodiesor antibody fragments (e.g. F(ab′)₂ bispecific antibodies). Techniquesfor generating bispecific antibodies from antibody fragments have beendescribed in the literature. For example, bispecific antibodies can beprepared using chemical linkage. Brennan et al., Science 229:81 (1985)describe a procedure wherein intact antibodies are proteolyticallycleaved to generate F(ab′)₂ fragments. These fragments are reduced inthe presence of the dithiol complexing agent sodium arsenite tostabilize vicinal dithiols and prevent intermolecular disulfideformation. The Fab′ fragments generated are then converted tothionitrobenzoate (TNB) derivatives. One of the Fab′-TNB derivatives isthen reconverted to the Fab′-thiol by reduction with mercaptoethylamineand is mixed with an equimolar amount of the other Fab′-TNB derivativeto form the bispecific antibody. The bispecific antibodies produced canbe used as agents for the selective immobilization of enzymes.

[0372] Fab′ fragments may be directly recovered from E. coli andchemically coupled to form bispecific antibodies. Shalaby et al., J.Exp. Med. 175:217 (1992) describe the production of a fully humanizedbispecific antibody F(ab′)₂ molecule. Each Fab′ fragment was separatelysecreted from E. coli and subjected to directed chemical coupling invitro to form the bispecific antibody. The bispecific antibody thusformed was able to bind to cells overexpressing the ErbB2 receptor andnormal human T cells, as well as trigger the lytic activity of humancytotoxic lymphocytes against human breast tumor targets.

[0373] Various technique for making and isolating bispecific antibodyfragments directly from recombinant cell culture have also beendescribed. For example, bispecific antibodies have been produced usingleucine zippers. Kostelny et al., J. Immunol. 148 (5):1547-1553 (1992).The leucine zipper peptides from the Fos and Jun proteins were linked tothe Fab′ portions of two different antibodies by gene fusion. Theantibody homodimers were reduced at the hinge region to form monomersand then re-oxidized to form the antibody heterodimers. This method canalso be utilized for the production of antibody homodimers. The“diabody” technology described by Hollinger et al., Proc. Natl. Acad.Sci. USA 90:6444-6448 (1993) has provided an alternative mechanism formaking bispecific antibody fragments. The fragments comprise aheavy-chain variable domain (V_(H)) connected to a light-chain variabledomain (V_(L)) by a linker which is too short to allow pairing betweenthe two domains on the same chain. Accordingly, the V_(H) and V_(L)domains of one fragment are forced to pair with the complementary V_(L)and V_(H) domains of another fragment, thereby forming twoantigen-binding sites. Another strategy for making bispecific antibodyfragments by the use of single-chain Fv (sFv) dimers has also beenreported. See, Gruber et al., J. Immunol. 152:5368 (1994). Antibodieswith more than two valencies are contemplated. For example, trispecificantibodies can be prepared. Tutt et al., J. Immunol. 147:60 (1991).

[0374] Exemplary bispecific antibodies may bind to two differentepitopes on a given PRO polypeptide herein. Alternatively, an anti-PROpolypeptide arm may be combined with an arm which binds to a triggeringmolecule on a leukocyte such as a T-cell receptor molecule (e.g. CD2,CD3, CD28, or B7), or Fc receptors for IgG (Fc γ R), such as Fc γ RI(CD64), Fc γ RII (CD32) and Fc γ RIII (CD16) so as to focus cellulardefense mechanisms to the cell expressing the particular PROpolypeptide. Bispecific antibodies may also be used to localizecytotoxic agents to cells which express a particular PRO polypeptide.These antibodies possess a PRO-binding arm and an arm which binds acytotoxic agent or a radionuclide chelator, such as EOTUBE, DPTA, DOTA,or TETA. Another bispecific antibody of interest binds the PROpolypeptide and further binds tissue factor (TF).

5. Heteroconjugate Antibodies

[0375] Heteroconjugate antibodies are also within the scope of thepresent invention. Heteroconjugate antibodies are composed of twocovalently joined antibodies. Such antibodies have, for example, beenproposed to target immune system cells to unwanted cells [U.S. Pat. No.4,676,980], and for treatment of HIV infection [WO 91/00360; WO92/200373; EP 03089]. It is contemplated that the antibodies may beprepared in vitro using known methods in synthetic protein chemistry,including those involving crosslinking agents. For example, immunotoxinsmay be constructed using a disulfide exchange reaction or by forming athioether bond. Examples of suitable reagents for this purpose includeiminothiolate and methyl-4-mercaptobutyrimidate and those disclosed, forexample, in U.S. Pat. No. 4,676,980.

6. Effector Function Engineering

[0376] It may be desirable to modify the antibody of the invention withrespect to effector function, so as to enhance, e.g., the effectivenessof the antibody in treating cancer. For example, cysteine residue(s) maybe introduced into the Fc region, thereby allowing interchain disulfidebond formation in this region. The homodimeric antibody thus generatedmay have improved internalization capability and/or increasedcomplement-mediated cell killing and antibody-dependent cellularcytotoxicity (ADCC). See Caron et al., J. Exp Med., 176: 1191-1195(1992) and Shopes, J. Immunol., 148: 2918-2922 (1992). Homodimericantibodies with enhanced anti-tumor activity may also be prepared usingheterobifunctional cross-linkers as described in Wolff et al. CancerResearch, 53: 2560-2565 (1993). Alternatively, an antibody can beengineered that has dual Fc regions and may thereby have enhancedcomplement lysis and ADCC capabilities. See Stevenson et al.,Anti-Cancer Drug Design, 3: 219-230 (1989).

7. Immunoconjugates

[0377] The invention also pertains to immunoconjugates comprising anantibody conjugated to a cytotoxic agent such as a chemotherapeuticagent, toxin (e.g., an enzymatically active toxin of bacterial, fungal,plant, or animal origin, or fragments thereof), or a radioactive isotope(i.e., a radioconjugate).

[0378] Chemotherapeutic agents useful in the generation of suchimmunoconjugates have been described above. Enzymatically active toxinsand fragments thereof that can be used include diphtheria A chain,nonbinding active fragments of diphtheria toxin, exotoxin A chain (fromPseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain,alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolacaamericana proteins (PAPI, PAPII, and PAP-S), momordica charantiainhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin,mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes. Avariety of radionuclides are available for the production ofradioconjugated antibodies. Examples include ²¹²Bi, ¹³¹I, ¹³¹In, ⁹⁰Y,and ¹⁸⁶Re. Conjugates of the antibody and cytotoxic agent are made usinga variety of bifunctional protein-coupling agents such asN-succinimidyl-3-(2-pyridyldithiol) propionate (SPDP), iminothiolane(IT), bifunctional derivatives of imidoesters (such as dimethyladipimidate HCL), active esters (such as disuccinimidyl suberate),aldehydes (such as glutareldehyde), bis-azido compounds (such as bis(p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such asbis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such astolyene 2,6-diisocyanate), and bis-active fluorine compounds (such as1,5-difluoro-2,4-dinitrobenzene). For example, a ricin immunotoxin canbe prepared as described in Vitetta et al., Science, 238: 1098 (1987).Carbon-14-labeled 1-isothiocyanatobenzyl-3-methyldiethylenetriaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent forconjugation of radionucleotide to the antibody. See WO 94/11026.

[0379] In another embodiment, the antibody may be conjugated to a“receptor” (such streptavidin) for utilization in tumor pretargetingwherein the antibody-receptor conjugate is administered to the patient,followed by removal of unbound conjugate from the circulation using aclearing agent and then administration of a “ligand” (e.g., avidin) thatis conjugated to a cytotoxic agent (e.g., a radionucleotide).

8. Immunoliposomes

[0380] The antibodies disclosed herein may also be formulated asimmunoliposomes. Liposomes containing the antibody are prepared bymethods known in the art, such as described in Epstein et al., Proc.Natl. Acad. Sci. USA, 82: 3688 (1985); Hwang et al., Proc. Natl Acad.Sci. USA, 77: 4030 (1980); and U.S. Pat. Nos. 4,485,045 and 4,544,545.Liposomes with enhanced circulation time are disclosed in U.S. Pat. No.5,013,556.

[0381] Particularly useful liposomes can be generated by thereverse-phase evaporation method with a lipid composition comprisingphosphatidylcholine, cholesterol, and PEG-derivatizedphosphatidylethanolamine (PEG-PE). Liposomes are extruded throughfilters of defined pore size to yield liposomes with the desireddiameter. Fab′ fragments of the antibody of the present invention can beconjugated to the liposomes as described in Martin et al., J. Biol.Chem., 257: 286-288 (1982) via a disulfide-interchange reaction. Achemotherapeutic agent (such as Doxorubicin) is optionally containedwithin the liposome. See Gabizon et al., J. National Cancer Inst.,81(19): 1484 (1989).

9. Pharmaceutical Compositions of Antibodies

[0382] Antibodies specifically binding a PRO polypeptide identifiedherein, as well as other molecules identified by the screening assaysdisclosed hereinbefore, can be administered for the treatment of variousdisorders in the form of pharmaceutical compositions.

[0383] If the PRO polypeptide is intracellular and whole antibodies areused as inhibitors, internalizing antibodies are preferred. However,lipofections or liposomes can also be used to deliver the antibody, oran antibody fragment, into cells. Where antibody fragments are used, thesmallest inhibitory fragment that specifically binds to the bindingdomain of the target protein is preferred. For example, based upon thevariable-region sequences of an antibody, peptide molecules can bedesigned that retain the ability to bind the target protein sequence.Such peptides can be synthesized chemically and/or produced byrecombinant DNA technology. See, e.g., Marasco et al., Proc. Natl. Acad.Sci. USA, 90: 7889-7893 (1993). The formulation herein may also containmore than one active compound as necessary for the particular indicationbeing treated, preferably those with complementary activities that donot adversely affect each other. Alternatively, or in addition, thecomposition may comprise an agent that enhances its function, such as,for example, a cytotoxic agent, cytokine, chemotherapeutic agent, orgrowth-inhibitory agent. Such molecules are suitably present incombination in amounts that are effective for the purpose intended.

[0384] The active ingredients may also be entrapped in microcapsulesprepared, for example, by coacervation techniques or by interfacialpolymerization, for example, hydroxymethylcellulose orgelatin-microcapsules and poly-(methylmethacylate) microcapsules,respectively, in colloidal drug delivery systems (for example,liposomes, albumin microspheres, microemulsions, nano-particles, andnanocapsules) or in macroemulsions. Such techniques are disclosed inRemington's Pharmaceutical Sciences, supra.

[0385] The formulations to be used for in vivo administration must besterile. This is readily accomplished by filtration through sterilefiltration membranes.

[0386] Sustained-release preparations may be prepared. Suitable examplesof sustained-release preparations include semipermeable matrices ofsolid hydrophobic polymers containing the antibody, which matrices arein the form of shaped articles, e.g., films, or microcapsules. Examplesof sustained-release matrices include polyesters, hydrogels (forexample, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)),polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acidand 65 ethyl-L-glutamate, non-degradable ethylene-vinyl acetate,degradable lactic acid-glycolic acid copolymers such as the LUPRONDEPOT™ (injectable microspheres composed of lactic acid-glycolic acidcopolymer and leuprolide acetate), and poly-D-(−)-3-hydroxybutyric acid.While polymers such as ethylene-vinyl acetate and lactic acid-glycolicacid enable release of molecules for over 100 days, certain hydrogelsrelease proteins for shorter time periods. When encapsulated antibodiesremain in the body for a long time, they may denature or aggregate as aresult of exposure to moisture at 37° C., resulting in a loss ofbiological activity and possible changes in immunogenicity. Rationalstrategies can be devised for stabilization depending on the mechanisminvolved. For example, if the aggregation mechanism is discovered to beintermolecular S—S bond formation through thio-disulfide interchange,stabilization may be achieved by modifying sulfhydryl residues,lyophilizing from acidic solutions, controlling moisture content, usingappropriate additives, and developing specific polymer matrixcompositions.

C. Uses for Anti-PRO Antibodies

[0387] The anti-PRO antibodies of the invention have various utilities.For example, anti-PRO antibodies may be used in diagnostic assays forPRO, e.g., detecting its expression (and in some cases, differentialexpression) in specific cells, tissues, or serum. Various diagnosticassay techniques known in the art may be used, such as competitivebinding assays, direct or indirect sandwich assays andimmunoprecipitation assays conducted in either heterogeneous orhomogeneous phases [Zola, Monoclonal Antibodies: A Manual of Techniques,CRC Press, Inc. (1987) pp.147-158]. The antibodies used in thediagnostic assays can be labeled with a detectable moiety. Thedetectable moiety should be capable of producing, either directly orindirectly, a detectable signal. For example, the detectable moiety maybe a radioisotope, such as ³H, ¹⁴C, ³²P, ³⁵S, or ¹²⁵I, a fluorescent orchemiluminescent compound, such as fluorescein isothiocyanate,rhodamine, or luciferin, or an enzyme, such as alkaline phosphatase,beta-galactosidase or horseradish peroxidase. Any method known in theart for conjugating the antibody to the detectable moiety may beemployed, including those methods described by Hunter et al., Nature,144:945 (1962); David et al., Biochemistry, 13:1014 (1974); Pain et al.,J. Immunol. Meth., 40:219 (1981); and Nygren, J. Histochem. andCytochem., 30:407 (1982).

[0388] Anti-PRO antibodies also are useful for the affinity purificationof PRO from recombinant cell culture or natural sources. In thisprocess, the antibodies against PRO are immobilized on a suitablesupport, such as Sephadex resin or filter paper, using methods wellknown in the art. The immobilized antibody then is contacted with asample containing the PRO to be purified, and thereafter the support iswashed with a suitable solvent that will remove substantially all thematerial in the sample except the PRO, which is bound to the immobilizedantibody. Finally, the support is washed with another suitable solventthat will release the PRO from the antibody.

[0389] The following examples are offered for illustrative purposesonly, and are not intended to limit the scope of the present inventionin any way.

[0390] All patent and literature references cited in the presentspecification are hereby incorporated by reference in their entirety.

EXAMPLES

[0391] Commercially available reagents referred to in the examples wereused according to manufacturer's instructions unless otherwiseindicated. The source of those cells identified in the followingexamples, and throughout the specification, by ATCC accession numbers isthe American Type Culture Collection, Manassas, Va.

Example 1 Extracellular Domain Homology Screening to Identify NovelPolypeptides and cDNA Encoding Therefor

[0392] The extracellular domain (ECD) sequences (including the secretionsignal sequence, if any) from about 950 known secreted proteins from theSwiss-Prot public database were used to search EST databases. The ESTdatabases included public databases (e.g., Dayhoff, GenBank), andproprietary databases (e.g. LIFESEQ™, Incyte Pharmaceuticals, Palo Alto,Calif.). The search was performed using the computer program BLAST orBLAST-2 (Altschul et al., Methods in Enzymology 266:460-480 (1996)) as acomparison of the ECD protein sequences to a 6 frame translation of theEST sequences. Those comparisons with a BLAST score of 70 (or in somecases 90) or greater that did not encode known proteins were clusteredand assembled into consensus DNA sequences with the program “phrap”(Phil Green, University of Washington, Seattle, Wash.).

[0393] Using this extracellular domain homology screen, consensus DNAsequences were assembled relative to the other identified EST sequencesusing phrap. In addition, the consensus DNA sequences obtained wereoften (but not always) extended using repeated cycles of BLAST orBLAST-2 and phrap to extend the consensus sequence as far as possibleusing the sources of EST sequences discussed above.

[0394] Based upon the consensus sequences obtained as described above,oligonucleotides were then synthesized and used to identify by PCR acDNA library that contained the sequence of interest and for use asprobes to isolate a clone of the full-length coding sequence for a PROpolypeptide. Forward and reverse PCR primers generally range from 20 to30 nucleotides and are often designed to give a PCR product of about100-1000 bp in length. The probe sequences are typically 40-55 bp inlength. In some cases, additional oligonucleotides are synthesized whenthe consensus sequence is greater than about 1-1.5 kbp. In order toscreen several libraries for a full-length clone, DNA from the librarieswas screened by PCR amplification, as per Ausubel et al., CurrentProtocols in Molecular Biology, with the PCR primer pair. A positivelibrary was then used to isolate clones encoding the gene of interestusing the probe oligonucleotide and one of the primer pairs.

[0395] The cDNA libraries used to isolate the cDNA clones wereconstructed by standard methods using commercially available reagentssuch as those from Invitrogen, San Diego, Calif. The cDNA was primedwith oligo dT containing a NotI site, linked with blunt to SalIhemikinased adaptors, cleaved with NotI, sized appropriately by gelelectrophoresis, and cloned in a defined orientation into a suitablecloning vector (such as pRKB or pRKD; pRK5B is a precursor of pRK5D thatdoes not contain the SfiI site; see, Holmes et al., Science,253:1278-1280 (1991)) in the unique XhoI and NotI sites.

Example 2 Isolation of cDNA Clones by Amylase Screening

[0396] 1. Preparation of oligo dT primed cDNA library

[0397] mRNA was isolated from a human tissue of interest using reagentsand protocols from Invitrogen, San Diego, Calif. (Fast Track 2). ThisRNA was used to generate an oligo dT primed cDNA library in the vectorpRK5D using reagents and protocols from Life Technologies, Gaithersburg,Md. (Super Script Plasmid System). In this procedure, the doublestranded cDNA was sized to greater than 1000 bp and the SalI/NotIlinkered cDNA was cloned into XhoI/NotI cleaved vector. pRK5D is acloning vector that has an sp6 transcription initiation site followed byan SfiI restriction enzyme site preceding the XhoI/NotI cDNA cloningsites.

[0398] 2. Preparation of random primed cDNA library

[0399] A secondary cDNA library was generated in order to preferentiallyrepresent the 5′ ends of the primary cDNA clones. Sp6 RNA was generatedfrom the primary library (described above), and this RNA was used togenerate a random primed cDNA library in the vector pSST-AMY.0 usingreagents and protocols from Life Technologies (Super Script PlasmidSystem, referenced above). In this procedure the double stranded cDNAwas sized to 500-1000 bp, linkered with blunt to NotI adaptors, cleavedwith SfiI, and cloned into SfiI/NotI cleaved vector. pSST-AMY.0 is acloning vector that has a yeast alcohol dehydrogenase promoter precedingthe cDNA cloning sites and the mouse amylase sequence (the maturesequence without the secretion signal) followed by the yeast alcoholdehydrogenase terminator, after the cloning sites. Thus, cDNAs clonedinto this vector that are fused in frame with amylase sequence will leadto the secretion of amylase from appropriately transfected yeastcolonies.

[0400] 3. Transformation and Detection

[0401] DNA from the library described in paragraph 2 above was chilledon ice to which was added electrocompetent DH10B bacteria (LifeTechnologies, 20 ml). The bacteria and vector mixture was thenelectroporated as recommended by the manufacturer. Subsequently, SOCmedia (Life Technologies, 1 ml) was added and the mixture was incubatedat 37° C. for 30 minutes. The transformants were then plated onto 20standard 150 mm LB plates containing ampicillin and incubated for 16hours (37° C.). Positive colonies were scraped off the plates and theDNA was isolated from the bacterial pellet using standard protocols,e.g. CsCl-gradient. The purified DNA was then carried on to the yeastprotocols below.

[0402] The yeast methods were divided into three categories: (1)Transformation of yeast with the plasmid/cDNA combined vector; (2)Detection and isolation of yeast clones secreting amylase; and (3) PCRamplification of the insert directly from the yeast colony andpurification of the DNA for sequencing and further analysis.

[0403] The yeast strain used was HD56-5A (ATCC-90785). This strain hasthe following genotype: MAT alpha, ura3-52, leu2-3, leu2-112, his3-11,his3-15, MAL⁺, SUC^(+ , GAL) ⁺. Preferably, yeast mutants can beemployed that have deficient post-translational pathways. Such mutantsmay have translocation deficient alleles in sec 71, sec 72, sec 62, withtruncated sec 71 being most preferred. Alternatively, antagonists(including antisense nucleotides and/or ligands) which interfere withthe normal operation of these genes, other proteins implicated in thispost translation pathway (e.g., SEC61p, SEC72p, SEC62p, SEC63p, TDJ1p orSSA1p-4p) or the complex formation of these proteins may also bepreferably employed in combination with the amylase-expressing yeast.

[0404] Transformation was performed based on the protocol outlined byGietz et al., Nucl. Acid. Res., 20:1425 (1992). Transformed cells werethen inoculated from agar into YEPD complex media broth (100 ml) andgrown overnight at 30° C. The YEPD broth was prepared as described inKaiser et al., Methods in Yeast Genetics, Cold Spring Harbor Press, ColdSpring Harbor, N.Y., p. 207 (1994). The overnight culture was thendiluted to about 2×10⁶ cells/ml (approx. OD₆₀₀=0.1) into fresh YEPDbroth (500 ml) and regrown to 1×10⁷ cells/ml (approx. OD₆₀₀=0.4-0.5).

[0405] The cells were then harvested and prepared for transformation bytransfer into GS3 rotor bottles in a Sorval GS3 rotor at 5,000 rpm for 5minutes, the supernatant discarded, and then resuspended into sterilewater, and centrifuged again in 50 ml falcon tubes at 3,500 rpm in aBeckman GS-6KR centrifuge. The supernatant was discarded and the cellswere subsequently washed with LiAc/TE (10 ml, 10 mM Tris-HCl, 1 mM EDTApH 7.5, 100 mM Li₂OOCCH₃), and resuspended into LiAc/TE (2.5 ml).

[0406] Transformation took place by mixing the prepared cells (100 μl)with freshly denatured single stranded salmon testes DNA (LofstrandLabs, Gaithersburg, Md.) and transforming DNA (1 μg, vol.<10 μl) inmicrofuge tubes. The mixture was mixed briefly by vortexing, then 40%PEG/TE (600 μl, 40% polyethylene glycol-4000, 10 mM Tris-HCl, 1 mM EDTA,100 mM Li₂OOCCH₃, pH 7.5) was added. This mixture was gently mixed andincubated at 30° C. while agitating for 30 minutes. The cells were thenheat shocked at 42° C. for 15 minutes, and the reaction vesselcentrifuged in a microfuge at 12,000 rpm for 5-10 seconds, decanted andresuspended into TE (500 μl, 10 mM Tris-HCl, 1 mM EDTA pH 7.5) followedby recentrifugation. The cells were then diluted into TE (1 ml) andaliquots (200 μl) were spread onto the selective media previouslyprepared in 150 mm growth plates (VWR).

[0407] Alternatively, instead of multiple small reactions, thetransformation was performed using a single, large scale reaction,wherein reagent amounts were scaled up accordingly.

[0408] The selective media used was a synthetic complete dextrose agarlacking uracil (SCD-Ura) prepared as described in Kaiser et al., Methodsin Yeast Genetics, Cold Spring Harbor Press, Cold Spring Harbor, N.Y.,p. 208-210 (1994). Transformants were grown at 30° C. for 2-3 days.

[0409] The detection of colonies secreting amylase was performed byincluding red starch in the selective growth media. Starch was coupledto the red dye (Reactive Red-120, Sigma) as per the procedure describedby Biely et al., Anal. Biochem., 172:176-179 (1988). The coupled starchwas incorporated into the SCD-Ura agar plates at a final concentrationof 0.15% (w/v), and was buffered with potassium phosphate to a pH of 7.0(50-100 mM final concentration).

[0410] The positive colonies were picked and streaked across freshselective media (onto 150 mm plates) in order to obtain well isolatedand identifiable single colonies. Well isolated single colonies positivefor amylase secretion were detected by direct incorporation of redstarch into buffered SCD-Ura agar. Positive colonies were determined bytheir ability to break down starch resulting in a clear halo around thepositive colony visualized directly.

[0411] 4. Isolation of DNA by PCR Amplification

[0412] When a positive colony was isolated, a portion of it was pickedby a toothpick and diluted into sterile water (30 μl) in a 96 wellplate. At this time, the positive colonies were either frozen and storedfor subsequent analysis or immediately amplified. An aliquot of cells (5μl) was used as a template for the PCR reaction in a 25 μl volumecontaining: 0.5 μl Klentaq (Clontech, Palo Alto, Calif.); 4.0 μl 10 mMdNTP's (Perkin Elmer-Cetus); 2.5 μl Kentaq buffer (Clontech); 0.25 μlforward oligo 1; 0.25 μl reverse oligo 2; 12.5 μl distilled water. Thesequence of the forward oligonucleotide 1 was:

[0413] 5′-TGTAAAACGACGGCCAGTTAAATAGACCTGCAATTATTAATCT-3′ (SEQ ID NO:169)

[0414] The sequence of reverse oligonucleotide 2 was:

[0415] 5′-CAGGAAACAGCTATGACCACCTGCACACCTGCAAATCCATT-3′ (SEQ ID NO:170)

[0416] PCR was then performed as follows: a. Denature 92° C.,  5 minutesb.  3 cycles of: Denature 92° C., 30 seconds Anneal 59° C., 30 secondsExtend 72° C., 60 seconds c.  3 cycles of: Denature 92° C., 30 secondsAnneal 57° C., 30 seconds Extend 72° C., 60 seconds d. 25 cycles of:Denature 92° C., 30 seconds Anneal 55° C., 30 seconds Extend 72° C., 60seconds e. Hold  4° C.

[0417] The underlined regions of the oligonucleotides annealed to theADH promoter region and the amylase region, respectively, and amplifieda 307 bp region from vector pSST-AMY.0 when no insert was present.Typically, the first 18 nucleotides of the 5′ end of theseoligonucleotides contained annealing sites for the sequencing primers.Thus, the total product of the PCR reaction from an empty vector was 343However, signal sequence-fused cDNA resulted in considerably longernucleotide sequences.

[0418] Following the PCR, an aliquot of the reaction (5 μl) was examinedby agarose gel electrophoresis in a 1% agarose gel using aTris-Borate-EDTA (TBE) buffering system as described by Sambrook et al.,supra. Clones resulting in a single strong PCR product larger than 400bp were further analyzed by DNA sequencing after purification with a 96Qiaquick PCR clean-up column (Qiagen Inc., Chatsworth, Calif.).

Example 3 Isolation of cDNA Clones Using Signal Algorithm Analysis

[0419] Various polypeptide-encoding nucleic acid sequences wereidentified by applying a proprietary signal sequence finding algorithmdeveloped by Genentech, Inc. (South San Francisco, Calif.) upon ESTs aswell as clustered and assembled EST fragments from public (e.g.,GenBank) and/or private (LIFESEQ®, Incyte Pharmaceuticals, Inc., PaloAlto, Calif.) databases. The signal sequence algorithm computes asecretion signal score based on the character of the DNA nucleotidessurrounding the first and optionally second methionine codon(s) (ATG) atthe 5′-end of the sequence or sequence fragment under consideration. Thenucleotides following the first ATG must code for at least 35unambiguous amino acids without any stop codons. If the first ATG hasthe required amino acids, the second is not examined. If neither meetsthe requirement, the candidate sequence is not scored. In order todetermine whether the EST sequence contains an authentic signalsequence, the DNA and corresponding amino acid sequences surrounding theATG codon are scored using a set of seven sensors (evaluationparameters) known to be associated with secretion signals. Use of thisalgorithm resulted in the identification of numerouspolypeptide-encoding nucleic acid sequences.

Example 4 Isolation of cDNA Clones Encoding Human PRO Polypeptides

[0420] Using the techniques described in Examples 1 to 3 above, numerousfull-length cDNA clones were identified as encoding PRO polypeptides asdisclosed herein. These cDNAs were then deposited under the terms of theBudapest Treaty with the American Type Culture Collection, 10801University Blvd., Manassas, Va. 20110-2209, USA (ATCC) as shown in Tabl7 below. TABLE 7 Material ATCC Dep. No. Deposit Date DNA26843-1389203099 Aug. 4,1998 DNA30867-1335 209807 Apr. 28, 1998 DNA34431-1177209399 Oct. 17, 1997 DNA38268-1188 209421 Oct. 28, 1997 DNA40621-1440209922 Jun. 2, 1998 DNA40625-1189 209788 Apr. 21, 1998 DNA45409-2511203579 Jan. 12,1999 DNA45495-1550 203156 Aug. 25, 1998 DNA49820-1427209932 Jun. 2, 1998 DNA56406-1704 203478 Nov. 17, 1998 DNA56410-1414209923 Jun. 2, 1998 DNA56436-1448 209902 May 27, 1998 DNA56855-1447203004 Jun. 23, 1998 DNA56860-1510 209952 Jun. 9, 1998 DNA56862-1343203174 Sep. 1, 1998 DNA56868-1478 203024 Jun. 23, 1998 DNA56869-1545203161 Aug. 25, 1998 DNA57704-1452 209953 Jun. 9, 1998 DNA58723-1588203133 Aug. 18, 1998 DNA57827-1493 203045 Jul. 1, 1998 DNA58737-1473203136 Aug. 18, 1998 DNA58846-1409 209957 Jun. 9, 1998 DNA58850-1495209956 Jun. 9, 1998 DNA58855-1422 203018 Jun. 23, 1998 DNA59211-1450209960 Jun. 9, 1998 DNA59212-1627 203245 Sep. 9, 1998 DNA59213-1487209959 Jun. 9, 1998 DNA59605-1418 203005 Jun. 23, 1998 DNA59609-1470209963 Jun. 9, 1998 DNA59610-1556 209990 Jun. 16, 1998 DNA59837-2545203658 Feb. 9, 1999 DNA59844-2542 203650 Feb. 9, 1999 DNA59854-1459209974 Jun. 16, 1998 DNA60625-1507 209975 Jun. 16, 1998 DNA60629-1481209979 Jun. 16, 1998 DNA61755-1554 203112 Aug. 11, 1998 DNA62812-1594203248 Sep. 9, 1998 DNA62815-1576 203247 Sep. 9, 1998 DNA64881-1602203240 Sep. 9, 1998 DNA64886-1601 203241 Sep. 9, 1998 DNA64902-1667203317 Oct. 6, 1998 DNA64950-1590 203224 Sep. 15, 1998 DNA65403-1565203230 Sep. 15, 1998 DNA66308-1537 203159 Aug. 25, 1998 DNA66519-1535203236 Sep. 15, 1998 DNA66521-1583 203225 Sep. 15, 1998 DNA66658-1584203229 Sep. 15, 1998 DNA66660-1585 203279 Sep. 22, 1998 DNA66663-1598203268 Sep. 22, 1998 DNA66674-1599 203281 Sep. 22, 1998 DNA68862-2546203652 Feb. 9, 1999 DNA68866-1644 203283 Sep. 22, 1998 DNA68871-1638203280 Sep. 22, 1998 DNA68880-1676 203319 Oct. 6, 1998 DNA68883-1691203535 Dec. 15, 1998 DNA68885-1678 203311 Oct. 6,1998 DNA71277-1636203285 Sep. 22, 1998 DNA73727-1673 203459 Nov. 3,1998 DNA73734-1680203363 Oct. 20, 1998 DNA73735-1681 203356 Oct. 20, 1998 DNA76393-1664203323 Oct. 6, 1998 DNA77301-1708 203407 Oct. 27, 1998 DNA77568-1626203134 Aug. 18, 1998 DNA77626-1705 203536 Dec. 15, 1998 DNA81754-2532203542 Dec. 15, 1998 DNA81757-2512 203543 Dec. 15, 1998 DNA82302-2529203534 Dec. 15, 1998 DNA82340-2530 203547 Dec. 22, 1998 DNA83500-2506203391 Oct. 29, 1998 DNA84920-2614 203966 Apr. 27, 1999 DNA85066-2534203588 Jan. 12, 1999 DNA86571-2551 203660 Feb. 9, 1999 DNA87991-2540203656 Feb. 9, 1999 DNA92238-2539 203602 Jan. 20, 1999 DNA96042-2682PTA-382 Jul. 20, 1999 DNA96787-2534 203589 Jan. 12, 1999 DNA125185-2806PTA-1031 Dec. 7, 1999 DNA147531-2821 PTA-1185 Jan. 11, 2000DNA115291-2681 PTA-202 Jun. 8, 1999 DNA164625-28890 PTA-1535 Mar. 21,2000 DNA131639-2874 PTA-1784 Apr. 25, 2000 DNA79230-2525 203549 Dec. 22,1998

[0421] These deposits were made under the provisions of the BudapestTreaty on the International Recognition of the Deposit of Microorganismsfor the Purpose of Patent Procedure and the Regulations thereunder(Budapest Treaty). This assures maintenance of a viable culture of thedeposit for 30 years from the date of deposit. The deposits will be madeavailable by ATCC under the terms of the Budapest Treaty, and subject toan agreement between Genentech, Inc. and ATCC, which assures permanentand unrestricted availability of the progeny of the culture of thedeposit to the public upon issuance of the pertinent U.S. patent or uponlaying open to the public of any U.S. or foreign patent application,whichever comes first, and assures availability of the progeny to onedetermined by the U.S. Commissioner of Patents and Trademarks to beentitled thereto according to 35 USC § 122 and the Commissioner's rulespursuant thereto (including 37 CFR § 1.14 with particular reference to886 OG 638).

[0422] The assignee of the present application has agreed that if aculture of the materials on deposit should die or be lost or destroyedwhen cultivated under suitable conditions, the materials will bepromptly replaced on notification with another of the same. Availabilityof the deposited material is not to be construed as a license topractice the invention in contravention of the rights granted under theauthority of any government in accordance with its patent laws.

Example 5 Use of PRO as a Hybridization Probe

[0423] The following method describes use of a nucleotide sequenceencoding PRO as a hybridization probe.

[0424] DNA comprising the coding sequence of full-length or mature PROas disclosed herein is employed as a probe to screen for homologous DNAs(such as those encoding naturally-occurring variants of PRO) in humantissue cDNA libraries or human tissue genomic libraries.

[0425] Hybridization and washing of filters containing either libraryDNAs is performed under the following high stringency conditions.Hybridization of radiolabeled PRO-derived probe to the filters isperformed in a solution of 50% formamide, 5×SSC, 0.1% SDS, 0.1% sodiumpyrophosphate, 50 mM sodium phosphate, pH 6.8, 2× Denhardt's solution,and 10% dextran sulfate at 42° C. for 20 hours. Washing of the filtersis performed in an aqueous solution of 0.1×SSC and 0.1% SDS at 42° C.

[0426] DNAs having a desired sequence identity with the DNA encodingfull-length native sequence PRO can then be identified using standardtechniques known in the art.

Example 6 Expression of PRO in E. Coli

[0427] This example illustrates preparation of an unglycosylated form ofPRO by recombinant expression in E. coli.

[0428] The DNA sequence encoding PRO is initially amplified usingselected PCR primers. The primers should contain restriction enzymesites which correspond to the restriction enzyme sites on the selectedexpression vector. A variety of expression vectors may be employed. Anexample of a suitable vector is pBR322 (derived from E. coli; seeBolivar et al., Gene, 2:95 (1977)) which contains genes for ampicillinand tetracycline resistance. The vector is digested with restrictionenzyme and dephosphorylated. The PCR amplified sequences are thenligated into the vector. The vector will preferably include sequenceswhich encode for an antibiotic resistance gene, a trp promoter, apolyhis leader (including the first six STII codons, polyhis sequence,and enterokinase cleavage site), the PRO coding region, lambdatranscriptional terminator, and an argU gene.

[0429] The ligation mixture is then used to transform a selected E. colistrain using the methods described in Sambrook et al., supra.Transformants are identified by their ability to grow on LB plates andantibiotic resistant colonies are then selected. Plasmid DNA can beisolated and confirmed by restriction analysis and DNA sequencing.

[0430] Selected clones can be grown overnight in liquid culture mediumsuch as LB broth supplemented with antibiotics. The overnight culturemay subsequently be used to inoculate a larger scale culture. The cellsare then grown to a desired optical density, during which the expressionpromoter is turned on.

[0431] After culturing the cells for several more hours, the cells canbe harvested by centrifugation. The cell pellet obtained by thecentrifugation can be solubilized using various agents known in the art,and the solubilized PRO protein can then be purified using a metalchelating column under conditions that allow tight binding of theprotein.

[0432] PRO may be expressed in E. coli in a poly-His tagged form, usingthe following procedure. The DNA encoding PRO is initially amplifiedusing selected PCR primers. The primers will contain restriction enzymesites which correspond to the restriction enzyme sites on the selectedexpression vector, and other useful sequences providing for efficientand reliable translation initiation, rapid purification on a metalchelation column, and proteolytic removal with enterokinase. ThePCR-amplified, poly-His tagged sequences are then ligated into anexpression vector, which is used to transform an E. coli host based onstrain 52 (W3110 fuhA(tonA) Ion galE rpoHts (htpRts) clpP(laclq).Transformants are first grown in LB containing 50 mg/ml carbenicillin at30° C. with shaking until an O.D.600 of 3-5 is reached. Cultures arethen diluted 50-100 fold into CRAP media (prepared by mixing 3.57 g(NH₄)₂SO₄, 0.71 g sodium citrate-2H2O, 1.07 g KCl, 5.36 g Difco yeastextract, 5.36 g Sheffield hycase SF in 500 mL water, as well as 110 mMMPOS, pH 7.3, 0.55% (w/v) glucose and 7 mM MgSO₄) and grown forapproximately 20-30 hours at 30° C. with shaking. Samples are removed toverify expression by SDS-page analysis, and the bulk culture iscentrifuged to pellet the cells. Cell pellets are frozen untilpurification and refolding.

[0433]E. coli paste from 0.5 to 1 L fermentations (6-10 g pellets) isresuspended in 10 volumes (w/v) in 7 M guanidine, 20 mM Tris, pH 8buffer. Solid sodium sulfite and sodium tetrathionate is added to makefinal concentrations of 0.1M and 0.02 M, respectively, and the solutionis stirred overnight at 4° C. This step results in a denatured proteinwith all cysteine residues blocked by sulfitolization. The solution iscentrifuged at 40,000 rpm in a Beckman Ultracentifuge for 30 min. Thesupernatant is diluted with 3-5 volumes of metal chelate column buffer(6 M guanidine, 20 mM Tris, pH 7.4) and filtered through 0.22 micronfilters to clarify. The clarified extract is loaded onto a 5 ml QiagenNi-NTA metal chelate column equilibrated in the metal chelate columnbuffer. The column is washed with additional buffer containing 50 mMimidazole (Calbiochem, Utrol grade), pH 7.4. The protein is eluted withbuffer containing 250 mM imidazole. Fractions containing the desiredprotein are pooled and stored at 4° C. Protein concentration isestimated by its absorbance at 280 nm using the calculated extinctioncoefficient based on its amino acid sequence.

[0434] The proteins are refolded by diluting the sample slowly intofreshly prepared refolding buffer consisting of: 20 mM Tris, pH 8.6, 0.3M NaCl, 2.5 M urea, 5 mM cysteine, 20 mM glycine and 1 mM EDTA.Refolding volumes are chosen so that the final protein concentration isbetween 50 to 100 micrograms/ml. The refolding solution is stirredgently at 4° C. for 12-36 hours. The refolding reaction is quenched bythe addition of TFA to a final concentration of 0.4% (pH ofapproximately 3). Before further purification of the protein, thesolution is filtered through a 0.22 micron filter and acetonitrile isadded to 2-10% final concentration. The refolded protein ischromatographed on a Poros R1/H reversed phase column using a mobilebuffer of 0.1% TFA with elution with a gradient of acetonitrile from 10to 80%. Aliquots of fractions with A280 absorbance are analyzed on SDSpolyacrylamide gels and fractions containing homogeneous refoldedprotein are pooled. Generally, the properly refolded species of mostproteins are eluted at the lowest concentrations of acetonitrile sincethose species are the most compact with their hydrophobic interiorsshielded from interaction with the reversed phase resin. Aggregatedspecies are usually eluted at higher acetonitrile concentrations. Inaddition to resolving misfolded forms of from the desired form, thereversed phase step also removes endotoxin from the samples.

[0435] Fractions containing the desired folded PRO polypeptide arepooled and the acetonitrile removed using a gentle stream of nitrogendirected at the solution. Proteins are formulated into 20 mM Hepes, pH6.8 with 0.14 M sodium chloride and 4% mannitol by dialysis or by gelfiltration using G25 Superfine (Pharmacia) resins equilibrated in theformulation buffer and sterile filtered.

[0436] Many of the PRO polypeptides disclosed herein were successfullyexpressed as described above.

Example 7 Expression of PRO in Mammalian Cells

[0437] This example illustrates preparation of a potentiallyglycosylated form of PRO by recombinant expression in mammalian cells.

[0438] The vector, pRK5 (see EP 307,247, published Mar. 15, 1989), isemployed as the expression vector. Optionally, the PRO DNA is ligatedinto pRK5 with selected restriction enzymes to allow insertion of thePRO DNA using ligation methods such as described in Sambrook et al.,supra. The resulting vector is called pRK5-PRO.

[0439] In one embodiment, the selected host cells may be 293 cells.Human 293 cells (ATCC CCL 1573) are grown to confluence in tissueculture plates in medium such as DMEM supplemented with fetal calf serumand optionally, nutrient components and/or antibiotics. About 10 μgpRK5-PRO DNA is mixed with about 1 μg DNA encoding the VA RNA gene[Thimmappaya et al., Cell, 31:543 (1982)] and dissolved in 500 μl of 1mM Tris-HCl, 0.1 mM EDTA, 0.227 M CaCl₂. To this mixture is added,dropwise, 500 μl of 50 mM HEPES (pH 7.35), 280 mM NaCl, 1.5 mM NaPO₄,and a precipitate is allowed to form for 10 minutes at 25° C. Theprecipitate is suspended and added to the 293 cells and allowed tosettle for about four hours at 37° C. The culture medium is aspiratedoff and 2 ml of 20% glycerol in PBS is added for 30 seconds. The 293cells are then washed with serum free medium, fresh medium is added andthe cells are incubated for about 5 days.

[0440] Approximately 24 hours after the transfections, the culturemedium is removed and replaced with culture medium (alone) or culturemedium containing 200 μCi/ml ³⁵S-cysteine and 200 μCi/ml ³⁵S-methionine.After a 12 hour incubation, the conditioned medium is collected,concentrated on a spin filter, and loaded onto a 15% SDS gel. Theprocessed gel may be dried and exposed to film for a selected period oftime to reveal the presence of PRO polypeptide. The cultures containingtransfected cells may undergo further incubation (in serum free medium)and the medium is tested in selected bioassays.

[0441] In an alternative technique, PRO may be introduced into 293 cellstransiently using the dextran sulfate method described by Somparyrac etal., Proc. Natl. Acad. Sci., 12:7575 (1981). 293 cells are grown tomaximal density in a spinner flask and 700 μg pRK5-PRO DNA is added. Thecells are first concentrated from the spinner flask by centrifugationand washed with PBS. The DNA-dextran precipitate is incubated on thecell pellet for four hours. The cells are treated with 20% glycerol for90 seconds, washed with tissue culture medium, and re-introduced intothe spinner flask containing tissue culture medium, 5 μg/ml bovineinsulin and 0.1 μg/ml bovine transferrin. After about four days, theconditioned media is centrifuged and filtered to remove cells anddebris. The sample containing expressed PRO can then be concentrated andpurified by any selected method, such as dialysis and/or columnchromatography.

[0442] In another embodiment, PRO can be expressed in CHO cells. ThepRK5-PRO can be transfected into CHO cells using known reagents such asCaPO₄ or DEAE-dextran. As described above, the cell cultures can beincubated, and the medium replaced with culture medium (alone) or mediumcontaining a radiolabel such as ³⁵S-methionine. After determining thepresence of PRO polypeptide, the culture medium may be replaced withserum free medium. Preferably, the cultures are incubated for about 6days, and then the conditioned medium is harvested. The mediumcontaining the expressed PRO can then be concentrated and purified byany selected method.

[0443] Epitope-tagged PRO may also be expressed in host CHO cells. ThePRO may be subcloned out of the pRK5 vector. The subclone insert canundergo PCR to fuse in frame with a selected epitope tag such as apoly-his tag into a Baculovirus expression vector. The poly-his taggedPRO insert can then be subcloned into a SV40 driven vector containing aselection marker such as DHFR for selection of stable clones. Finally,the CHO cells can be transfected (as described above) with the SV40driven vector. Labeling may be performed, as described above, to verifyexpression. The culture medium containing the expressed poly-His taggedPRO can then be concentrated and purified by any selected method, suchas by Ni²⁺-chelate affinity chromatography.

[0444] PRO may also be expressed in CHO and/or COS cells by a transientexpression procedure or in CHO cells by another stable expressionprocedure.

[0445] Stable expression in CHO cells is performed using the followingprocedure. The proteins are expressed as an IgG construct(immunoadhesin), in which the coding sequences for the soluble forms(e.g. extracellular domains) of the respective proteins are fused to anIgG1 constant region sequence containing the hinge, CH2 and CH2 domainsand/or is a poly-His tagged form.

[0446] Following PCR amplification, the respective DNAs are subcloned ina CHO expression vector using standard techniques as described inAusubel et al., Current Protocols of Molecular Biology, Unit 3.16, JohnWiley and Sons (1997). CHO expression vectors are constructed to havecompatible restriction sites 5′ and 3′ of the DNA of interest to allowthe convenient shuttling of cDNA's. The vector used expression in CHOcells is as described in Lucas et al., Nucl. Acids Res. 24:9 (1774-1779(1996), and uses the SV40 early promoter/enhancer to drive expression ofthe cDNA of interest and dihydrofolate reductase (DHFR). DHFR expressionpermits selection for stable maintenance of the plasmid followingtransfection.

[0447] Twelve micrograms of the desired plasmid DNA is introduced intoapproximately 10 million CHO cells using commercially availabletransfection reagents Superfect® (Quiagen), Dosper® or Fugene®(Boehringer Mannheim). The cells are grown as described in Lucas et al.,supra. Approximately 3×10⁻⁷ cells are frozen in an ampule for furthergrowth and production as described below.

[0448] The ampules containing the plasmid DNA are thawed by placementinto water bath and mixed by vortexing. The contents are pipetted into acentrifuge tube containing 10 mLs of media and centrifuged at 1000 rpmfor 5 minutes. The supernatant is aspirated and the cells areresuspended in 10 mL of selective media (0.2 μm filtered PS20 with 5%0.2 μm diafiltered fetal bovine serum). The cells are then aliquotedinto a 100 mL spinner containing 90 mL of selective media. After 1-2days, the cells are transferred into a 250 mL spinner filled with 150 mLselective growth medium and incubated at 37° C. After another 2-3 days,250 mL, 500 mL and 2000 mL spinners are seeded with 3×10⁵ cells/mL. Thecell media is exchanged with fresh media by centrifugation andresuspension in production medium. Although any suitable CHO media maybe employed, a production medium described in U.S. Pat. No. 5,122,469,issued Jun. 16, 1992 may actually be used. A 3L production spinner isseeded at 1.2×10⁶ cells/mL. On day 0, the cell number pH is determined.On day 1, the spinner is sampled and sparging with filtered air iscommenced. On day 2, the spinner is sampled, the temperature shifted to33° C., and 30 mL of 500 g/L glucose and 0.6 mL of 10% antifoam (e.g.,35% polydimethylsiloxane emulsion, Dow Corning 365 Medical GradeEmulsion) taken. Throughout the production, the pH is adjusted asnecessary to keep it at around 7.2. After 10 days, or until theviability dropped below 70%, the cell culture is harvested bycentrifugation and filtering through a 0.22 μm filter. The filtrate waseither stored at 4° C. or immediately loaded onto columns forpurification.

[0449] For the poly-His tagged constructs, the proteins are purifiedusing a Ni-NTA column (Qiagen). Before purification, imidazole is addedto the conditioned media to a concentration of 5 mM. The conditionedmedia is pumped onto a 6 ml Ni-NTA column equilibrated in 20 mM Hepes,pH 7.4, buffer containing 0.3 M NaCl and 5 mM imidazole at a flow rateof 4-5 ml/min. at 4° C. After loading, the column is washed withadditional equilibration buffer and the protein eluted withequilibration buffer containing 0.25 M imidazole. The highly purifiedprotein is subsequently desalted into a storage buffer containing 10 mMHepes, 0.14 M NaCl and 4% mannitol, pH 6.8, with a 25 ml G25 Superfine(Pharmacia) column and stored at −80° C.

[0450] Immunoadhesin (Fc-containing) constructs are purified from theconditioned media as follows. The conditioned medium is pumped onto a 5ml Protein A column (Pharmacia) which had been equilibrated in 20 mM Naphosphate buffer, pH 6.8. After loading, the column is washedextensively with equilibration buffer before elution with 100 mM citricacid, pH 3.5. The eluted protein is immediately neutralized bycollecting 1 ml fractions into tubes containing 275 μL of 1 M Trisbuffer, pH 9. The highly purified protein is subsequently desalted intostorage buffer as described above for the poly-His tagged proteins. Thehomogeneity is assessed by SDS polyacrylamide gels and by N-terminalamino acid sequencing by Edman degradation.

[0451] Many of the PRO polypeptides disclosed herein were successfullyexpressed as described above.

Example 8 Expression of PRO in Yeast

[0452] The following method describes recombinant expression of PRO inyeast.

[0453] First, yeast expression vectors are constructed for intracellularproduction or secretion of PRO from the ADH2/GAPDH promoter. DNAencoding PRO and the promoter is inserted into suitable restrictionenzyme sites in the selected plasmid to direct intracellular expressionof PRO. For secretion, DNA encoding PRO can be cloned into the selectedplasmid, together with DNA encoding the ADH2/GAPDH promoter, a nativePRO signal peptide or other mammalian signal peptide, or, for example, ayeast alpha-factor or invertase secretory signal/leader sequence, andlinker sequences (if needed) for expression of PRO.

[0454] Yeast cells, such as yeast strain AB110, can then be transformedwith the expression plasmids described above and cultured in selectedfermentation media. The transformed yeast supernatants can be analyzedby precipitation with 10% trichloroacetic acid and separation bySDS-PAGE, followed by staining of the gels with Coomassie Blue stain.

[0455] Recombinant PRO can subsequently be isolated and purified byremoving the cells from the fermentation medium by centrifugation andthen concentrating the medium using selected cartridge filters. Theconcentrate containing PRO may further be purified using selected columnchromatography resins.

[0456] Many of the PRO polypeptides disclosed herein were successfullyexpressed as described above.

Example 9 Expression of PRO in Baculovirus-Infected Insect Cells

[0457] The following method describes recombinant expression of PRO inBaculovirus-infected insect cells.

[0458] The sequence coding for PRO is fused upstream of an epitope tagcontained a baculovirus expression vector. Such epitope tags includepoly-his tags and immunoglobulin tags (like Fc regions of IgG). Avariety of plasmids may be employed, including plasmids derived fromcommercially available plasmids such as pVL1393 (Novagen). Briefly, thesequence encoding PRO or the desired portion of the coding sequence ofPRO such as the sequence encoding the extracellular domain of atransmembrane protein or the sequence encoding the mature protein if theprotein is extracellular is amplified by PCR with primers complementaryto the 5′ and 3′ regions. The 5′ primer may incorporate flanking(selected) restriction enzyme sites. The product is then digested withthose selected restriction enzymes and subcloned into the expressionvector.

[0459] Recombinant baculovirus is generated by co-transfecting the aboveplasmid and BaculoGold™ virus DNA (Pharmingen) into Spodopterafrugiperda (“Sf9”) cells (ATCC CRL 1711) using lipofectin (commerciallyavailable from GIBCO-BRL). After 4-5 days of incubation at 28° C., thereleased viruses are harvested and used for further amplifications.Viral infection and protein expression are performed as described byO'Reilley et al., Baculovirus expression vectors: A Laboratory Manual,Oxford: Oxford University Press (1994).

[0460] Expressed poly-his tagged PRO can then be purified, for example,by Ni²⁺-chelate affinity chromatography as follows. Extracts areprepared from recombinant virus-infected Sf9 cells as described byRupert et al., Nature, 362:175-179 (1993). Briefly, Sf9 cells arewashed, resuspended in sonication buffer (25 mL Hepes, pH 7.9; 12.5 mMMgCl₂; 0.1 mM EDTA; 10% glycerol; 0.1% NP-40; 0.4 M KCl), and sonicatedtwice for 20 seconds on ice. The sonicates are cleared bycentrifugation, and the supernatant is diluted 50-fold in loading buffer(50 mM phosphate, 300 mM NaCl, 10% glycerol, pH 7.8) and filteredthrough a 0.45 μm filter. A Ni²⁺-NTA agarose column (commerciallyavailable from Qiagen) is prepared with a bed volume of 5 mL, washedwith 25 mL of water and equilibrated with 25 mL of loading buffer. Thefiltered cell extract is loaded onto the column at 0.5 mL per minute.The column is washed to baseline A₂₈₀ with loading buffer, at whichpoint fraction collection is started. Next, the column is washed with asecondary wash buffer (50 mM phosphate; 300 mM NaCl, 10% glycerol, pH6.0), which elutes nonspecifically bound protein. After reaching A₂₈₀baseline again, the column is developed with a 0 to 500 mM Imidazolegradient in the secondary wash buffer. One mL fractions are collectedand analyzed by SDS-PAGE and silver staining or Western blot withNi²⁺-NTA-conjugated to alkaline phosphatase (Qiagen). Fractionscontaining the eluted His₁₀-tagged PRO are pooled and dialyzed againstloading buffer.

[0461] Alternatively, purification of the IgG tagged (or Fc tagged) PROcan be performed using known chromatography techniques, including forinstance, Protein A or protein G column chromatography.

[0462] Many of the PRO polypeptides disclosed herein were successfullyexpressed as described above.

Example 10 Preparation of Antibodies That Bind PRO

[0463] This example illustrates preparation of monoclonal antibodieswhich can specifically bind PRO.

[0464] Techniques for producing the monoclonal antibodies are known inthe art and are described, for instance, in Goding, supra. Immunogensthat may be employed include purified PRO, fusion proteins containingPRO, and cells expressing recombinant PRO on the cell surface. Selectionof the immunogen can be made by the skilled artisan without undueexperimentation.

[0465] Mice, such as Balb/c, are immunized with the PRO immunogenemulsified in complete Freund's adjuvant and injected subcutaneously orintraperitoneally in an amount from 1-100 micrograms. Alternatively, theimmunogen is emulsified in MPL-TDM adjuvant (Ribi ImmunochemicalResearch, Hamilton, Mont.) and injected into the animal's hind footpads. The immunized mice are then boosted 10 to 12 days later withadditional immunogen emulsified in the selected adjuvant. Thereafter,for several weeks, the mice may also be boosted with additionalimmunization injections. Serum samples may be periodically obtained fromthe mice by retro-orbital bleeding for testing in ELISA assays to detectanti-PRO antibodies.

[0466] After a suitable antibody titer has been detected, the animals“positive”for antibodies can be injected with a final intravenousinjection of PRO. Three to four days later, the mice are sacrificed andthe spleen cells are harvested. The spleen cells are then fused (using35% polyethylene glycol) to a selected murine myeloma cell line such asP3X63AgU.1, available from ATCC, No. CRL 1597. The fusions generatehybridoma cells which can then be plated in 96 well tissue cultureplates containing HAT (hypoxanthine, aminopterin, and thymidine) mediumto inhibit proliferation of non-fused cells, myeloma hybrids, and spleencell hybrids.

[0467] The hybridoma cells will be screened in an ELISA for reactivityagainst PRO. Determination of “positive” hybridoma cells secreting thedesired monoclonal antibodies against PRO is within the skill in theart.

[0468] The positive hybridoma cells can be injected intraperitoneallyinto syngeneic Balb/c mice to produce ascites containing the anti-PROmonoclonal antibodies. Alternatively, the hybridoma cells can be grownin tissue culture flasks or roller bottles. Purification of themonoclonal antibodies produced in the ascites can be accomplished usingammonium sulfate precipitation, followed by gel exclusionchromatography. Alternatively, affinity chromatography based uponbinding of antibody to protein A or protein G can be employed.

Example 11 Purification of PRO Polypeptides Using Specific Antibodies

[0469] Native or recombinant PRO polypeptides may be purified by avariety of standard techniques in the art of protein purification. Forexample, pro-PRO polypeptide, mature PRO polypeptide, or pre-PROpolypeptide is purified by immunoaffinity chromatography usingantibodies specific for the PRO polypeptide of interest. In general, animmunoaffinity column is constructed by covalently coupling the anti-PROpolypeptide antibody to an activated chromatographic resin.

[0470] Polyclonal immunoglobulins are prepared from immune sera eitherby precipitation with ammonium sulfate or by purification on immobilizedProtein A (Pharmacia LKB Biotechnology, Piscataway, N.J.). Likewise,monoclonal antibodies are prepared from mouse ascites fluid by ammoniumsulfate precipitation or chromatography on immobilized Protein A.Partially purified immunoglobulin is covalently attached to achromatographic resin such as CnBr-activated SEPHAROSE™ (Pharmacia LKBBiotechnology). The antibody is coupled to the resin, the resin isblocked, and the derivative resin is washed according to themanufacturer's instructions.

[0471] Such an immunoaffinity column is utilized in the purification ofPRO polypeptide by preparing a fraction from cells containing PROpolypeptide in a soluble form. This preparation is derived bysolubilization of the whole cell or of a subcellular fraction obtainedvia differential centrifugation by the addition of detergent or by othermethods well known in the art. Alternatively, soluble PRO polypeptidecontaining a signal sequence may be secreted in useful quantity into themedium in which the cells are grown.

[0472] A soluble PRO polypeptide-containing preparation is passed overthe immunoaffinity column, and the column is washed under conditionsthat allow the preferential absorbance of PRO polypeptide (e.g., highionic strength buffers in the presence of detergent). Then, the columnis eluted under conditions that disrupt antibody/PRO polypeptide binding(e.g., a low pH buffer such as approximately pH 2-3, or a highconcentration of a chaotrope such as urea or thiocyanate ion), and PROpolypeptide is collected.

Example 12 Drug Screening

[0473] This invention is particularly useful for screening compounds byusing PRO polypeptides or binding fragment thereof in any of a varietyof drug screening techniques. The PRO polypeptide or fragment employedin such a test may either be free in solution, affixed to a solidsupport, borne on a cell surface, or located intracellularly. One methodof drug screening utilizes eukaryotic or prokaryotic host cells whichare stably transformed with recombinant nucleic acids expressing the PROpolypeptide or fragment. Drugs are screened against such transformedcells in competitive binding assays. Such cells, either in viable orfixed form, can be used for standard binding assays. One may measure,for example, the formation of complexes between PRO polypeptide or afragment and the agent being tested. Alternatively, one can examine thediminution in complex formation between the PRO polypeptide and itstarget cell or target receptors caused by the agent being tested.

[0474] Thus, the present invention provides methods of screening fordrugs or any other agents which can affect a PRO polypeptide-associateddisease or disorder. These methods comprise contacting such an agentwith a PRO polypeptide or fragment thereof and assaying (I) for thepresence of a complex between the agent and the PRO polypeptide orfragment, or (ii) for the presence of a complex between the PROpolypeptide or fragment and the cell, by methods well known in the art.In such competitive binding assays, the PRO polypeptide or fragment istypically labeled. After suitable incubation, free PRO polypeptide orfragment is separated from that present in bound form, and the amount offree or uncomplexed label is a measure of the ability of the particularagent to bind to PRO polypeptide or to interfere with the PROpolypeptide/cell complex.

[0475] Another technique for drug screening provides high throughputscreening for compounds having suitable binding affinity to apolypeptide and is described in detail in WO 84/03564, published on Sep.13, 1984. Briefly stated, large numbers of different small peptide testcompounds are synthesized on a solid substrate, such as plastic pins orsome other surface. As applied to a PRO polypeptide, the peptide testcompounds are reacted with PRO polypeptide and washed. Bound PROpolypeptide is detected by methods well known in the art. Purified PROpolypeptide can also be coated directly onto plates for use in theaforementioned drug screening techniques. In addition, non-neutralizingantibodies can be used to capture the peptide and immobilize it on thesolid support.

[0476] This invention also contemplates the use of competitive drugscreening assays in which neutralizing antibodies capable of binding PROpolypeptide specifically compete with a test compound for binding to PROpolypeptide or fragments thereof. In this manner, the antibodies can beused to detect the presence of any peptide which shares one or moreantigenic determinants with PRO polypeptide.

Example 13 Rational Drug Design

[0477] The goal of rational drug design is to produce structural analogsof biologically active polypeptide of interest (i.e., a PRO polypeptide)or of small molecules with which they interact, e.g., agonists,antagonists, or inhibitors. Any of these examples can be used to fashiondrugs which are more active or stable forms of the PRO polypeptide orwhich enhance or interfere with the function of the PRO polypeptide invivo (c.f., Hodgson, Bio/Technology, 9: 19-21(1991)).

[0478] In one approach, the three-dimensional structure of the PROpolypeptide, or of a PRO polypeptide-inhibitor complex, is determined byX-ray crystallography, by computer modeling or, most typically, by acombination of the two approaches. Both the shape and charges of the PROpolypeptide must be ascertained to elucidate the structure and todetermine active site(s) of the molecule. Less often, useful informationregarding the structure of the PRO polypeptide may be gained by modelingbased on the structure of homologous proteins. In both cases, relevantstructural information is used to design analogous PRO polypeptide-likemolecules or to identify efficient inhibitors. Useful examples ofrational drug design may include molecules which have improved activityor stability as shown by Braxton and Wells, Biochemistry, 31:7796-7801(1992) or which act as inhibitors, agonists, or antagonists of nativepeptides as shown by Athauda et al., J. Biochem., 113:742-746(1993).

[0479] It is also possible to isolate a target-specific antibody,selected by functional assay, as described above, and then to solve itscrystal structure. This approach, in principle, yields a pharmacore uponwhich subsequent drug design can be based. It is possible to bypassprotein crystallography altogether by generating anti-idiotypicantibodies (anti-ids) to a functional, pharmacologically activeantibody. As a mirror image of a mirror image, the binding site of theanti-ids would be expected to be an analog of the original receptor. Theanti-id could then be used to identify and isolate peptides from banksof chemically or biologically produced peptides. The isolated peptideswould then act as the pharmacore.

[0480] By virtue of the present invention, sufficient amounts of the PROpolypeptide may be made available to perform such analytical studies asX-ray crystallography. In addition, knowledge of the PRO polypeptideamino acid sequence provided herein will provide guidance to thoseemploying computer modeling techniques in place of or in addition toX-ray crystallography.

Example 14 Pericyte c-Fos Induction (Assay 93)

[0481] This assay shows that certain polypeptides of the invention actto induce the expression of c-fos in pericyte cells and, therefore, areuseful not only as diagnostic markers for particular types ofpericyte-associated tumors but also for giving rise to antagonists whichwould be expected to be useful for the therapeutic treatment ofpericyte-associated tumors. Induction of c-fos expression in pericytesis also indicative of the induction of angiogenesis and, as such, PROpolypeptides capable of inducing the expression of c-fos would beexpected to be useful for the treatment of conditions where inducedangiogenesis would be beneficial including, for example, wound healing,and the like. Specifically, on day 1, pericytes are received from VECTechnologies and all but 5 ml of media is removed from flask. On day 2,the pericytes are trypsinized, washed, spun and then plated onto 96 wellplates. On day 7, the media is removed and the pericytes are treatedwith 100 μl of PRO polypeptide test samples and controls (positivecontrol=DME+5% serum±PDGF at 500 ng/ml; negative control=protein 32).Replicates are averaged and SD/CV are determined. Fold increase overProtein 32 (buffer control) value indicated by chemiluminescence units(RLU) luminometer reading verses frequency is plotted on a histogram.Two-fold above Protein 32 value is considered positive for the assay.ASY Matrix: Growth media=low glucose DMEM=20% FBS+1× pen strep+1×fungizone. Assay Media=low glucose DMEM+5% FBS.

[0482] The following polypeptides tested positive in this assay: PRO1347and PRO1340.

Example 15 Ability of PRO Polypeptides to Stimulate the Release ofProteoglycans from Cartilage (Assay 97)

[0483] The ability of various PRO polypeptides to stimulate the releaseof proteoglycans from cartilage tissue was tested as follows.

[0484] The metacarphophalangeal joint of 4-6 month old pigs wasaseptically dissected, and articular cartilage was removed by free handslicing being careful to avoid the underlying bone. The cartilage wasminced and cultured in bulk for 24 hours in a humidified atmosphere of95% air, 5% CO₂ in serum free (SF) media (DME/F12 1:1) with 0.1% BSA and100 U/ml penicillin and 100 μg/ml streptomycin. After washing threetimes, approximately 100 mg of articular cartilage was aliquoted intomicronics tubes and incubated for an additional 24 hours in the above SFmedia. PRO polypeptides were then added at 1% either alone or incombination with 18 ng/ml interleukin-1α, a known stimulator ofproteoglycan release from cartilage tissue. The supernatant was thenharvested and assayed for the amount of proteoglycans using the1,9-dimethyl-methylene blue (DMB) colorimetric assay (Farndale andButtle, Biochem. Biophys. Acta 883:173-177 (1985)). A positive result inthis assay indicates that the test polypeptide will find use, forexample, in the treatment of sports-related joint problems, articularcartilage defects, osteoarthritis or rheumatoid arthritis.

[0485] When various PRO polypeptides were tested in the above assay, thepolypeptides demonstrated a marked ability to stimulate release ofproteoglycans from cartilage tissue both basally and after stimulationwith interleukin-1α and at 24 and 72 hours after treatment, therebyindicating that these PRO polypeptides are useful for stimulatingproteoglycan release from cartilage tissue. As such, these PROpolypeptides are useful for the treatment of sports-related jointproblems, articular cartilage defects, osteoarthritis or rheumatoidarthritis. The polypeptides testing positive in this assay are: PRO1565,PRO1693, PRO1801 and PRO10096.

Example 16 Detection of Polypeptides That Affect Glucose or FFA Uptakein Skeletal Muscle (Assay 106)

[0486] This assay is designed to determine whether PRO polypeptides showthe ability to affect glucose or FFA uptake by skeletal muscle cells.PRO polypeptides testing positive in this assay would be expected to beuseful for the therapeutic treatment of disorders where either thestimulation or inhibition of glucose uptake by skeletal muscle would bebeneficial including, for example, diabetes or hyper- orhypo-insulinemia.

[0487] In a 96 well format, PRO polypeptides to be assayed are added toprimary rat differentiated skeletal muscle, and allowed to incubateovernight. Then fresh media with the PRO polypeptide and ±insulin areadded to the wells. The sample media is then monitored to determineglucose and FFA uptake by the skeletal muscle cells. The insulin willstimulate glucose and FFA uptake by the skeletal muscle, and insulin inmedia without the PRO polypeptide is used as a positive control, and alimit for scoring. As the PRO polypeptide being tested may eitherstimulate or inhibit glucose and FFA uptake, results are scored aspositive in the assay if greater than 1.5 times or less than 0.5 timesthe insulin control.

[0488] The following PRO polypeptides tested positive as eitherstimulators or inhibitors of glucose and/or FFA uptake in this assay:PRO4405.

Example 17 Identification of PRO Polypeptides That Stimulate TNF-αRelease In Human Blood (Assay 128)

[0489] This assay shows that certain PRO polypeptides of the presentinvention act to stimulate the release of TNF-α in human blood. PROpolypeptides testing positive in this assay are useful for, among otherthings, research purposes where stimulation of the release of TNF-αwould be desired and for the therapeutic treatment of conditions whereinenhanced TNF-α release would be beneficial. Specifically, 200 μl ofhuman blood supplemented with 50 mM Hepes buffer (pH 7.2) is aliquottedper well in a 96 well test plate. To each well is then added 300 μl ofeither the test PRO polypeptide in 50 mM Hepes buffer (at variousconcentrations) or 50 mM Hepes buffer alone (negative control) and theplates are incubated at 37° C. for 6 hours. The samples are thencentrifuged and 50 μl of plasma is collected from each well and testedfor the presence of TNF-α by ELISA assay. A positive in the assay is ahigher amount of TNF-α in the PRO polypeptide treated samples ascompared to the negative control samples.

[0490] The following PRO polypeptides tested positive in this assay:PRO263, PRO295, PRO1282, PRO1063, PRO1356, PRO3543, and PRO5990.

Example 18 Tumor Versus Normal Differential Tissue ExpressionDistribution

[0491] Oligonucleotide probes were constructed from some of the PROpolypeptide-encoding nucleotide sequences shown in the accompanyingfigures for use in quantitative PCR amplification reactions. Theoligonucleotide probes were chosen so as to give an approximately200-600 base pair amplified fragment from the 3′ end of its associatedtemplate in a standard PCR reaction. The oligonucleotide probes wereemployed in standard quantitative PCR amplification reactions with cDNAlibraries isolated from different human tumor and normal human tissuesamples and analyzed by agarose gel electrophoresis so as to obtain aquantitative determination of the level of expression of the PROpolypeptide-encoding nucleic acid in the various tumor and normaltissues tested. β-actin was used as a control to assure that equivalentamounts of nucleic acid was used in each reaction. Identification of thedifferential expression of the PRO polypeptide-encoding nucleic acid inone or more tumor tissues as compared to one or more normal tissues ofthe same tissue type renders the molecule useful diagnostically for thedetermination of the presence or absence of tumor in a subject suspectedof possessing a tumor as well as therapeutically as a target for thetreatment of a tumor in a subject possessing such a tumor. These assaysprovided the following results. Molecule is more highly expressed in: ascompared to: DNA26843-1389 normal lung lung rumor rectum tumor normalrectum DNA30867-1335 normal kidney kidney tumor DNA40621-1440 normallung lung rumor DNA40625-1189 normal lung lung tumor DNA45409-2511melanoma tumor normal akin DNA56406-1704 kidney tumor normal kidneynormal skin melanoma rumor DNA56410-1414 normal stomach stomach tumorDNA56436-1448 normal skin melanoma tumor DNA56855-1447 normal esophagusesophageal tumor rectum tumor normal rectum DNA56860-1510 normal kidneykidney rumor rectum tumor normal rectum DNA56862-1343 kidney tumornormal kidney normal lung lung rumor DNA56868-1478 normal stomachstomach tumor normal lung lung rumor DNA56869-1545 normal esophagusesophageal tumor normal skin melanoma tumor DNA57704-1452 normal stomachstomach tumor rectum rumor normal rectum DNA58723-1588 normal stomachstomach tumor kidney rumor normal kidney normal akin melanoma tumorDNA57827-1493 normal stomach stomach tumor normal skin melanoma tumorDNA58737-1473 esophageal tumor normal esophagus normal stomach stomachtumor DNA58846-1409 lung tumor normal lung DNA58850-1495 esophagealtumor normal esophagus kidney tumor normal kidney DNA58855-1422 normalstomach stomach tumor rectum tumor normal rectum DNA59211-1450 normalkidney kidney tumor DNA59212-1627 normal skin melanoma tumorDNA59213-1487 normal stomach stomach tumor normal skin melanoma tumorDNA59605-1418 melanoma rumor normal skin DNA59609-1470 esophageal tumornormal esophagus DNA59610-1556 esophageal rumor normal esophagus lungtumor normal lung normal skin melanoma tumor DNA59837-2545 normal skinmelanoma tumor DNA59844-2542 normal skin melanoma tumor esophageal tumornormal esophagus DNA59854-1459 normal esophagus esophageal tumor stomachtumor normal stomach normal lung lung tumor DNA60625-1507 normal lunglung rumor DNA60629-1481 normal esophagus esophageal tumor normal rectumrectum tumor DNA61755-1554 normal stomach stomach tumor kidney tumornormal kidney DNA62812-1594 normal stomach stomach tumor normal lunglung tumor normal rectum rectum tumor normal skin melanoma tumorDNA62815-1576 esophageal tumor normal esophagus DNA64881-1602 normalstomach stomach tumor normal lung lung tumor DNA64902-1667 esophagealtumor normal esophagus kidney tumor normal kidney DNA65403-1565 normalesophagus esophageal tumor DNA66308-1537 normal lung lung tumorDNA66519-1535 kidney tumor normal kidney DNA66521-1583 normal esophagusesophageal tumor normal stomach stomach tumor normal lung lung tumornormal rectum rectum tumor normal skin melanoma tumor DNA66658-1584normal lung lung rumor melanoma tumor normal skin DNA66660-1585 lungrumor normal lung DNA66674-1599 kidney tumor normal kidney normal lunglung tumor DNA68862-2546 melanoma tumor normal skin DNA68866-1644 normalstomach stomach tumor DNA68871-1638 lung tumor normal lung normal skinmelanoma tumor DNA68880-1676 normal lung lung tumor normal skin melanomatumor DNA68883-1691 esophageal rumor normal esophagus DNA68885-1678 lungtumor normal lung DNA71277-1636 normal stomach stomach tumorDNA73734-1680 normal lung lung tumor DNA73735-1681 esophageal tumornormal esophagus normal kidney kidney tumor lung tumor normal lungnormal skin melanoma tumor DNA76393-1664 esophageal rumor normalesophagus stomach rumor normal stomach lung tumor normal lung rectumrumor normal rectum DNA77568-1626 normal stomach stomach rumor lungrumor normal lung DNA77626-1705 normal rectum rectum rumor DNA81754-2532normal skin melanoma rumor DNA81757-2512 esophageal tumor normalesophagus normal stomach stomach rumor melanoma tumor normal skinDNA82302-2529 normal stomach stomach rumor normal lung lung rumorDNA82340-2530 normal esophagus esophageal rumor DNA85066-2534 lung tumornormal lung normal skin melanoma rumor DNA87991-2540 esophageal rumornormal esophagus DNA92238-2539 normal skin melanoma rumor DNA96787-2534normal kidney kidney rumor

Example 19 Identification of Receptor/Ligand Interactions

[0492] In this assay, various PRO polypeptides are tested for ability tobind to a panel of potential receptor or ligand molecules for thepurpose of identifying receptor/ligand interactions. The identificationof a ligand for a known receptor, a receptor for a known ligand or anovel receptor/ligand pair is useful for a variety of indicationsincluding, for example, targeting bioactive molecules (linked to theligand or receptor) to a cell known to express the receptor or ligand,use of the receptor or ligand as a reagent to detect the presence of theligand or receptor in a composition suspected of containing the same,wherein the composition may comprise cells suspected of expressing theligand or receptor, modulating the growth of or another biological orimmunological activity of a cell known to express or respond to thereceptor or ligand, modulating the immune response of cells or towardcells that express the receptor or ligand, allowing the preparation ofagonists, antagonists and/or antibodies directed against the receptor orligand which will modulate the growth of or a biological orimmunological activity of a cell expressing the receptor or ligand, andvarious other indications which will be readily apparent to theordinarily skilled artisan.

[0493] The assay is performed as follows. A PRO polypeptide of thepresent invention suspected of being a ligand for a receptor isexpressed as a fusion protein containing the Fc domain of human IgG (animmunoadhesin). Receptor-ligand binding is detected by allowinginteraction of the immunoadhesin polypeptide with cells (e.g. Cos cells)expressing candidate PRO polypeptide receptors and visualization ofbound immunoadhesin with fluorescent reagents directed toward the Fcfusion domain and examination by microscope. Cells expressing candidatereceptors are produced by transient transfection, in parallel, ofdefined subsets of a library of cDNA expression vectors encoding PROpolypeptides that may function as receptor molecules. Cells are thenincubated for 1 hour in the presence of the PRO polypeptideimmunoadhesin being tested for possible receptor binding. The cells arethen washed and fixed with paraformaldehyde. The cells are thenincubated with fluorescent conjugated antibody directed against the Fcportion of the PRO polypeptide immunoadhesin (e.g. FITC conjugated goatanti-human-Fc antibody). The cells are then washed again and examined bymicroscope. A positive interaction is judged by the presence offluorescent labeling of cells transfected with cDNA encoding aparticular PRO polypeptide receptor or pool of receptors and an absenceof similar fluorescent labeling of similarly prepared cells that havebeen transfected with other cDNA or pools of cDNA. If a defined pool ofcDNA expression vectors is judged to be positive for interaction with aPRO polypeptide immunoadhesin, the individual cDNA species that comprisethe pool are tested individually (the pool is “broken down”) todetermine the specific cDNA that encodes a receptor able to interactwith the PRO polypeptide immunoadhesin.

[0494] In another embodiment of this assay, an epitope-tagged potentialligand PRO polypeptide (e.g. 8 histidine “His” tag) is allowed tointeract with a panel of potential receptor PRO polypeptide moleculesthat have been expressed as fusions with the Fc domain of human IgG(immunoadhesins). Following a 1 hour co-incubation with the epitopetagged PRO polypeptide, the candidate receptors are eachimmunoprecipitated with protein A beads and the beads are washed.Potential ligand interaction is determined by western blot analysis ofthe immunoprecipitated complexes with antibody directed towards theepitope tag. An interaction is judged to occur if a band of theanticipated molecular weight of the epitope tagged protein is observedin the western blot analysis with a candidate receptor, but is notobserved to occur with the other members of the panel of potentialreceptors.

[0495] Using these assays, the following receptor/ligand interactionshave been herein identified:

[0496] (1) PRO10272 binds to PRO5801.

[0497] (2) PRO20110 binds to the human IL-17 receptor (Yao et al.,Cytokine 9(11):794-800 (1997); also herein designated as PRO1) and toPRO20040.

[0498] (3) PRO10096 binds to PRO20233.

[0499] (4) PRO19670 binds to PRO1890.

[0500] The foregoing written specification is considered to besufficient to enable one skilled in the art to practice the invention.The present invention is not to be limited in scope by the constructdeposited, since the deposited embodiment is intended as a singleillustration of certain aspects of the invention and any constructs thatare functionally equivalent are within the scope of this invention. Thedeposit of material herein does not constitute an admission that thewritten description herein contained is inadequate to enable thepractice of any aspect of the invention, including the best modethereof, nor is it to be construed as limiting the scope of the claimsto the specific illustrations that it represents. Indeed, variousmodifications of the invention in addition to those shown and describedherein will become apparent to those skilled in the art from theforegoing description and fall within the scope of the appended claims.

1 170 1 1173 DNA Homo Sapien 1 ggggcttcgg cgccagcggc cagcgctagtcggtctggta aggatttaca 50 aaaggtgcag gtatgagcag gtctgaagac taacattttgtgaagttgta 100 aaacagaaaa cctgttagaa atgtggtggt ttcagcaagg cctcagtttc150 cttccttcag cccttgtaat ttggacatct gctgctttca tattttcata 200cattactgca gtaacactcc accatataga cccggcttta ccttatatca 250 gtgacactggtacagtagct ccagaaaaat gcttatttgg ggcaatgcta 300 aatattgcgg cagttttatgcattgctacc atttatgttc gttataagca 350 agttcatgct ctgagtcctg aagagaacgttatcatcaaa ttaaacaagg 400 ctggccttgt acttggaata ctgagttgtt taggactttctattgtggca 450 aacttccaga aaacaaccct ttttgctgca catgtaagtg gagctgtgct500 tacctttggt atgggctcat tatatatgtt tgttcagacc atcctttcct 550accaaatgca gcccaaaatc catggcaaac aagtcttctg gatcagactg 600 ttgttggttatctggtgtgg agtaagtgca cttagcatgc tgacttgctc 650 atcagttttg cacagtggcaattttgggac tgatttagaa cagaaactcc 700 attggaaccc cgaggacaaa ggttatgtgcttcacatgat cactactgca 750 gcagaatggt ctatgtcatt ttccttcttt ggttttttcctgacttacat 800 tcgtgatttt cagaaaattt ctttacgggt ggaagccaat ttacatggat850 taaccctcta tgacactgca ccttgcccta ttaacaatga acgaacacgg 900ctactttcca gagatatttg atgaaaggat aaaatatttc tgtaatgatt 950 atgattctcagggattgggg aaaggttcac agaagttgct tattcttctc 1000 tgaaattttc aaccacttaatcaaggctga cagtaacact gatgaatgct 1050 gataatcagg aaacatgaaa gaagccatttgatagattat tctaaaggat 1100 atcatcaaga agactattaa aaacacctat gcctatacttttttatctca 1150 gaaaataaag tcaaaagact atg 1173 2 266 PRT Homo Sapien 2Met Trp Trp Phe Gln Gln Gly Leu Ser Phe Leu Pro Ser Ala Leu 1 5 10 15Val Ile Trp Thr Ser Ala Ala Phe Ile Phe Ser Tyr Ile Thr Ala 20 25 30 ValThr Leu His His Ile Asp Pro Ala Leu Pro Tyr Ile Ser Asp 35 40 45 Thr GlyThr Val Ala Pro Glu Lys Cys Leu Phe Gly Ala Met Leu 50 55 60 Asn Ile AlaAla Val Leu Cys Ile Ala Thr Ile Tyr Val Arg Tyr 65 70 75 Lys Gln Val HisAla Leu Ser Pro Glu Glu Asn Val Ile Ile Lys 80 85 90 Leu Asn Lys Ala GlyLeu Val Leu Gly Ile Leu Ser Cys Leu Gly 95 100 105 Leu Ser Ile Val AlaAsn Phe Gln Lys Thr Thr Leu Phe Ala Ala 110 115 120 His Val Ser Gly AlaVal Leu Thr Phe Gly Met Gly Ser Leu Tyr 125 130 135 Met Phe Val Gln ThrIle Leu Ser Tyr Gln Met Gln Pro Lys Ile 140 145 150 His Gly Lys Gln ValPhe Trp Ile Arg Leu Leu Leu Val Ile Trp 155 160 165 Cys Gly Val Ser AlaLeu Ser Met Leu Thr Cys Ser Ser Val Leu 170 175 180 His Ser Gly Asn PheGly Thr Asp Leu Glu Gln Lys Leu His Trp 185 190 195 Asn Pro Glu Asp LysGly Tyr Val Leu His Met Ile Thr Thr Ala 200 205 210 Ala Glu Trp Ser MetSer Phe Ser Phe Phe Gly Phe Phe Leu Thr 215 220 225 Tyr Ile Arg Asp PheGln Lys Ile Ser Leu Arg Val Glu Ala Asn 230 235 240 Leu His Gly Leu ThrLeu Tyr Asp Thr Ala Pro Cys Pro Ile Asn 245 250 255 Asn Glu Arg Thr ArgLeu Leu Ser Arg Asp Ile 260 265 3 2037 DNA Homo Sapien 3 cggacgcgtgggcggacgcg tgggggagag ccgcagtccc ggctgcagca 50 cctgggagaa ggcagaccgtgtgagggggc ctgtggcccc agcgtgctgt 100 ggcctcgggg agtgggaagt ggaggcaggagccttcctta cacttcgcca 150 tgagtttcct catcgactcc agcatcatga ttacctcccagatactattt 200 tttggatttg ggtggctttt cttcatgcgc caattgttta aagactatga250 gatacgtcag tatgttgtac aggtgatctt ctccgtgacg tttgcatttt 300cttgcaccat gtttgagctc atcatctttg aaatcttagg agtattgaat 350 agcagctcccgttattttca ctggaaaatg aacctgtgtg taattctgct 400 gatcctggtt ttcatggtgcctttttacat tggctatttt attgtgagca 450 atatccgact actgcataaa caacgactgcttttttcctg tctcttatgg 500 ctgaccttta tgtatttctt ctggaaacta ggagatccctttcccattct 550 cagcccaaaa catgggatct tatccataga acagctcatc agccgggttg600 gtgtgattgg agtgactctc atggctcttc tttctggatt tggtgctgtc 650aactgcccat acacttacat gtcttacttc ctcaggaatg tgactgacac 700 ggatattctagccctggaac ggcgactgct gcaaaccatg gatatgatca 750 taagcaaaaa gaaaaggatggcaatggcac ggagaacaat gttccagaag 800 ggggaagtgc ataacaaacc atcaggtttctggggaatga taaaaagtgt 850 taccacttca gcatcaggaa gtgaaaatct tactcttattcaacaggaag 900 tggatgcttt ggaagaatta agcaggcagc tttttctgga aacagctgat950 ctatatgcta ccaaggagag aatagaatac tccaaaacct tcaaggggaa 1000atattttaat tttcttggtt actttttctc tatttactgt gtttggaaaa 1050 ttttcatggctaccatcaat attgtttttg atcgagttgg gaaaacggat 1100 cctgtcacaa gaggcattgagatcactgtg aattatctgg gaatccaatt 1150 tgatgtgaag ttttggtccc aacacatttccttcattctt gttggaataa 1200 tcatcgtcac atccatcaga ggattgctga tcactcttaccaagttcttt 1250 tatgccatct ctagcagtaa gtcctccaat gtcattgtcc tgctattagc1300 acagataatg ggcatgtact ttgtctcctc tgtgctgctg atccgaatga 1350gtatgccttt agaataccgc accataatca ctgaagtcct tggagaactg 1400 cagttcaacttctatcaccg ttggtttgat gtgatcttcc tggtcagcgc 1450 tctctctagc atactcttcctctatttggc tcacaaacag gcaccagaga 1500 agcaaatggc accttgaact taagcctactacagactgtt agaggccagt 1550 ggtttcaaaa tttagatata agagggggga aaaatggaaccagggcctga 1600 cattttataa acaaacaaaa tgctatggta gcatttttca ccttcatagc1650 atactccttc cccgtcaggt gatactatga ccatgagtag catcagccag 1700aacatgagag ggagaactaa ctcaagacaa tactcagcag agagcatccc 1750 gtgtggatatgaggctggtg tagaggcgga gaggagccaa gaaactaaag 1800 gtgaaaaata cactggaactctggggcaag acatgtctat ggtagctgag 1850 ccaaacacgt aggatttccg ttttaaggttcacatggaaa aggttatagc 1900 tttgccttga gattgactca ttaaaatcag agactgtaacaaaaaaaaaa 1950 aaaaaaaaaa agggcggccg cgactctaga gtcgacctgc agaagcttgg2000 ccgccatggc ccaacttgtt tattgcagct tataatg 2037 4 455 PRT Homo Sapien4 Met Ser Phe Leu Ile Asp Ser Ser Ile Met Ile Thr Ser Gln Ile 1 5 10 15Leu Phe Phe Gly Phe Gly Trp Leu Phe Phe Met Arg Gln Leu Phe 20 25 30 LysAsp Tyr Glu Ile Arg Gln Tyr Val Val Gln Val Ile Phe Ser 35 40 45 Val ThrPhe Ala Phe Ser Cys Thr Met Phe Glu Leu Ile Ile Phe 50 55 60 Glu Ile LeuGly Val Leu Asn Ser Ser Ser Arg Tyr Phe His Trp 65 70 75 Lys Met Asn LeuCys Val Ile Leu Leu Ile Leu Val Phe Met Val 80 85 90 Pro Phe Tyr Ile GlyTyr Phe Ile Val Ser Asn Ile Arg Leu Leu 95 100 105 His Lys Gln Arg LeuLeu Phe Ser Cys Leu Leu Trp Leu Thr Phe 110 115 120 Met Tyr Phe Phe TrpLys Leu Gly Asp Pro Phe Pro Ile Leu Ser 125 130 135 Pro Lys His Gly IleLeu Ser Ile Glu Gln Leu Ile Ser Arg Val 140 145 150 Gly Val Ile Gly ValThr Leu Met Ala Leu Leu Ser Gly Phe Gly 155 160 165 Ala Val Asn Cys ProTyr Thr Tyr Met Ser Tyr Phe Leu Arg Asn 170 175 180 Val Thr Asp Thr AspIle Leu Ala Leu Glu Arg Arg Leu Leu Gln 185 190 195 Thr Met Asp Met IleIle Ser Lys Lys Lys Arg Met Ala Met Ala 200 205 210 Arg Arg Thr Met PheGln Lys Gly Glu Val His Asn Lys Pro Ser 215 220 225 Gly Phe Trp Gly MetIle Lys Ser Val Thr Thr Ser Ala Ser Gly 230 235 240 Ser Glu Asn Leu ThrLeu Ile Gln Gln Glu Val Asp Ala Leu Glu 245 250 255 Glu Leu Ser Arg GlnLeu Phe Leu Glu Thr Ala Asp Leu Tyr Ala 260 265 270 Thr Lys Glu Arg IleGlu Tyr Ser Lys Thr Phe Lys Gly Lys Tyr 275 280 285 Phe Asn Phe Leu GlyTyr Phe Phe Ser Ile Tyr Cys Val Trp Lys 290 295 300 Ile Phe Met Ala ThrIle Asn Ile Val Phe Asp Arg Val Gly Lys 305 310 315 Thr Asp Pro Val ThrArg Gly Ile Glu Ile Thr Val Asn Tyr Leu 320 325 330 Gly Ile Gln Phe AspVal Lys Phe Trp Ser Gln His Ile Ser Phe 335 340 345 Ile Leu Val Gly IleIle Ile Val Thr Ser Ile Arg Gly Leu Leu 350 355 360 Ile Thr Leu Thr LysPhe Phe Tyr Ala Ile Ser Ser Ser Lys Ser 365 370 375 Ser Asn Val Ile ValLeu Leu Leu Ala Gln Ile Met Gly Met Tyr 380 385 390 Phe Val Ser Ser ValLeu Leu Ile Arg Met Ser Met Pro Leu Glu 395 400 405 Tyr Arg Thr Ile IleThr Glu Val Leu Gly Glu Leu Gln Phe Asn 410 415 420 Phe Tyr His Arg TrpPhe Asp Val Ile Phe Leu Val Ser Ala Leu 425 430 435 Ser Ser Ile Leu PheLeu Tyr Leu Ala His Lys Gln Ala Pro Glu 440 445 450 Lys Gln Met Ala Pro455 5 2372 DNA Homo Sapien 5 agcagggaaa tccggatgtc tcggttatga agtggagcagtgagtgtgag 50 cctcaacata gttccagaac tctccatccg gactagttat tgagcatctg 100cctctcatat caccagtggc catctgaggt gtttccctgg ctctgaaggg 150 gtaggcacgatggccaggtg cttcagcctg gtgttgcttc tcacttccat 200 ctggaccacg aggctcctggtccaaggctc tttgcgtgca gaagagcttt 250 ccatccaggt gtcatgcaga attatggggatcacccttgt gagcaaaaag 300 gcgaaccagc agctgaattt cacagaagct aaggaggcctgtaggctgct 350 gggactaagt ttggccggca aggaccaagt tgaaacagcc ttgaaagcta400 gctttgaaac ttgcagctat ggctgggttg gagatggatt cgtggtcatc 450tctaggatta gcccaaaccc caagtgtggg aaaaatgggg tgggtgtcct 500 gatttggaaggttccagtga gccgacagtt tgcagcctat tgttacaact 550 catctgatac ttggactaactcgtgcattc cagaaattat caccaccaaa 600 gatcccatat tcaacactca aactgcaacacaaacaacag aatttattgt 650 cagtgacagt acctactcgg tggcatcccc ttactctacaatacctgccc 700 ctactactac tcctcctgct ccagcttcca cttctattcc acggagaaaa750 aaattgattt gtgtcacaga agtttttatg gaaactagca ccatgtctac 800agaaactgaa ccatttgttg aaaataaagc agcattcaag aatgaagctg 850 ctgggtttggaggtgtcccc acggctctgc tagtgcttgc tctcctcttc 900 tttggtgctg cagctggtcttggattttgc tatgtcaaaa ggtatgtgaa 950 ggccttccct tttacaaaca agaatcagcagaaggaaatg atcgaaacca 1000 aagtagtaaa ggaggagaag gccaatgata gcaaccctaatgaggaatca 1050 aagaaaactg ataaaaaccc agaagagtcc aagagtccaa gcaaaactac1100 cgtgcgatgc ctggaagctg aagtttagat gagacagaaa tgaggagaca 1150cacctgaggc tggtttcttt catgctcctt accctgcccc agctggggaa 1200 atcaaaagggccaaagaacc aaagaagaaa gtccaccctt ggttcctaac 1250 tggaatcagc tcaggactgccattggacta tggagtgcac caaagagaat 1300 gcccttctcc ttattgtaac cctgtctggatcctatcctc ctacctccaa 1350 agcttcccac ggcctttcta gcctggctat gtcctaataatatcccactg 1400 ggagaaagga gttttgcaaa gtgcaaggac ctaaaacatc tcatcagtat1450 ccagtggtaa aaaggcctcc tggctgtctg aggctaggtg ggttgaaagc 1500caaggagtca ctgagaccaa ggctttctct actgattccg cagctcagac 1550 cctttcttcagctctgaaag agaaacacgt atcccacctg acatgtcctt 1600 ctgagcccgg taagagcaaaagaatggcag aaaagtttag cccctgaaag 1650 ccatggagat tctcataact tgagacctaatctctgtaaa gctaaaataa 1700 agaaatagaa caaggctgag gatacgacag tacactgtcagcagggactg 1750 taaacacaga cagggtcaaa gtgttttctc tgaacacatt gagttggaat1800 cactgtttag aacacacaca cttacttttt ctggtctcta ccactgctga 1850tattttctct aggaaatata cttttacaag taacaaaaat aaaaactctt 1900 ataaatttctatttttatct gagttacaga aatgattact aaggaagatt 1950 actcagtaat ttgtttaaaaagtaataaaa ttcaacaaac atttgctgaa 2000 tagctactat atgtcaagtg ctgtgcaaggtattacactc tgtaattgaa 2050 tattattcct caaaaaattg cacatagtag aacgctatctgggaagctat 2100 ttttttcagt tttgatattt ctagcttatc tacttccaaa ctaattttta2150 tttttgctga gactaatctt attcattttc tctaatatgg caaccattat 2200aaccttaatt tattattaac atacctaaga agtacattgt tacctctata 2250 taccaaagcacattttaaaa gtgccattaa caaatgtatc actagccctc 2300 ctttttccaa caagaagggactgagagatg cagaaatatt tgtgacaaaa 2350 aattaaagca tttagaaaac tt 2372 6322 PRT Homo Sapien 6 Met Ala Arg Cys Phe Ser Leu Val Leu Leu Leu ThrSer Ile Trp 1 5 10 15 Thr Thr Arg Leu Leu Val Gln Gly Ser Leu Arg AlaGlu Glu Leu 20 25 30 Ser Ile Gln Val Ser Cys Arg Ile Met Gly Ile Thr LeuVal Ser 35 40 45 Lys Lys Ala Asn Gln Gln Leu Asn Phe Thr Glu Ala Lys GluAla 50 55 60 Cys Arg Leu Leu Gly Leu Ser Leu Ala Gly Lys Asp Gln Val Glu65 70 75 Thr Ala Leu Lys Ala Ser Phe Glu Thr Cys Ser Tyr Gly Trp Val 8085 90 Gly Asp Gly Phe Val Val Ile Ser Arg Ile Ser Pro Asn Pro Lys 95 100105 Cys Gly Lys Asn Gly Val Gly Val Leu Ile Trp Lys Val Pro Val 110 115120 Ser Arg Gln Phe Ala Ala Tyr Cys Tyr Asn Ser Ser Asp Thr Trp 125 130135 Thr Asn Ser Cys Ile Pro Glu Ile Ile Thr Thr Lys Asp Pro Ile 140 145150 Phe Asn Thr Gln Thr Ala Thr Gln Thr Thr Glu Phe Ile Val Ser 155 160165 Asp Ser Thr Tyr Ser Val Ala Ser Pro Tyr Ser Thr Ile Pro Ala 170 175180 Pro Thr Thr Thr Pro Pro Ala Pro Ala Ser Thr Ser Ile Pro Arg 185 190195 Arg Lys Lys Leu Ile Cys Val Thr Glu Val Phe Met Glu Thr Ser 200 205210 Thr Met Ser Thr Glu Thr Glu Pro Phe Val Glu Asn Lys Ala Ala 215 220225 Phe Lys Asn Glu Ala Ala Gly Phe Gly Gly Val Pro Thr Ala Leu 230 235240 Leu Val Leu Ala Leu Leu Phe Phe Gly Ala Ala Ala Gly Leu Gly 245 250255 Phe Cys Tyr Val Lys Arg Tyr Val Lys Ala Phe Pro Phe Thr Asn 260 265270 Lys Asn Gln Gln Lys Glu Met Ile Glu Thr Lys Val Val Lys Glu 275 280285 Glu Lys Ala Asn Asp Ser Asn Pro Asn Glu Glu Ser Lys Lys Thr 290 295300 Asp Lys Asn Pro Glu Glu Ser Lys Ser Pro Ser Lys Thr Thr Val 305 310315 Arg Cys Leu Glu Ala Glu Val 320 7 2586 DNA Homo Sapien 7 cgccgcgctcccgcacccgc ggcccgccca ccgcgccgct cccgcatctg 50 cacccgcagc ccggcggcctcccggcggga gcgagcagat ccagtccggc 100 ccgcagcgca actcggtcca gtcggggcggcggctgcggg cgcagagcgg 150 agatgcagcg gcttggggcc accctgctgt gcctgctgctggcggcggcg 200 gtccccacgg cccccgcgcc cgctccgacg gcgacctcgg ctccagtcaa250 gcccggcccg gctctcagct acccgcagga ggaggccacc ctcaatgaga 300tgttccgcga ggttgaggaa ctgatggagg acacgcagca caaattgcgc 350 agcgcggtggaagagatgga ggcagaagaa gctgctgcta aagcatcatc 400 agaagtgaac ctggcaaacttacctcccag ctatcacaat gagaccaaca 450 cagacacgaa ggttggaaat aataccatccatgtgcaccg agaaattcac 500 aagataacca acaaccagac tggacaaatg gtcttttcagagacagttat 550 cacatctgtg ggagacgaag aaggcagaag gagccacgag tgcatcatcg600 acgaggactg tgggcccagc atgtactgcc agtttgccag cttccagtac 650acctgccagc catgccgggg ccagaggatg ctctgcaccc gggacagtga 700 gtgctgtggagaccagctgt gtgtctgggg tcactgcacc aaaatggcca 750 ccaggggcag caatgggaccatctgtgaca accagaggga ctgccagccg 800 gggctgtgct gtgccttcca gagaggcctgctgttccctg tgtgcacacc 850 cctgcccgtg gagggcgagc tttgccatga ccccgccagccggcttctgg 900 acctcatcac ctgggagcta gagcctgatg gagccttgga ccgatgccct950 tgtgccagtg gcctcctctg ccagccccac agccacagcc tggtgtatgt 1000gtgcaagccg accttcgtgg ggagccgtga ccaagatggg gagatcctgc 1050 tgcccagagaggtccccgat gagtatgaag ttggcagctt catggaggag 1100 gtgcgccagg agctggaggacctggagagg agcctgactg aagagatggc 1150 gctgggggag cctgcggctg ccgccgctgcactgctggga ggggaagaga 1200 tttagatctg gaccaggctg tgggtagatg tgcaatagaaatagctaatt 1250 tatttcccca ggtgtgtgct ttaggcgtgg gctgaccagg cttcttccta1300 catcttcttc ccagtaagtt tcccctctgg cttgacagca tgaggtgttg 1350tgcatttgtt cagctccccc aggctgttct ccaggcttca cagtctggtg 1400 cttgggagagtcaggcaggg ttaaactgca ggagcagttt gccacccctg 1450 tccagattat tggctgctttgcctctacca gttggcagac agccgtttgt 1500 tctacatggc tttgataatt gtttgaggggaggagatgga aacaatgtgg 1550 agtctccctc tgattggttt tggggaaatg tggagaagagtgccctgctt 1600 tgcaaacatc aacctggcaa aaatgcaaca aatgaatttt ccacgcagtt1650 ctttccatgg gcataggtaa gctgtgcctt cagctgttgc agatgaaatg 1700ttctgttcac cctgcattac atgtgtttat tcatccagca gtgttgctca 1750 gctcctacctctgtgccagg gcagcatttt catatccaag atcaattccc 1800 tctctcagca cagcctggggagggggtcat tgttctcctc gtccatcagg 1850 gatctcagag gctcagagac tgcaagctgcttgcccaagt cacacagcta 1900 gtgaagacca gagcagtttc atctggttgt gactctaagctcagtgctct 1950 ctccactacc ccacaccagc cttggtgcca ccaaaagtgc tccccaaaag2000 gaaggagaat gggatttttc ttgaggcatg cacatctgga attaaggtca 2050aactaattct cacatccctc taaaagtaaa ctactgttag gaacagcagt 2100 gttctcacagtgtggggcag ccgtccttct aatgaagaca atgatattga 2150 cactgtccct ctttggcagttgcattagta actttgaaag gtatatgact 2200 gagcgtagca tacaggttaa cctgcagaaacagtacttag gtaattgtag 2250 ggcgaggatt ataaatgaaa tttgcaaaat cacttagcagcaactgaaga 2300 caattatcaa ccacgtggag aaaatcaaac cgagcagggc tgtgtgaaac2350 atggttgtaa tatgcgactg cgaacactga actctacgcc actccacaaa 2400tgatgttttc aggtgtcatg gactgttgcc accatgtatt catccagagt 2450 tcttaaagtttaaagttgca catgattgta taagcatgct ttctttgagt 2500 tttaaattat gtataaacataagttgcatt tagaaatcaa gcataaatca 2550 cttcaactgc aaaaaaaaaa aaaaaaaaaaaaaaaa 2586 8 350 PRT Homo Sapien 8 Met Gln Arg Leu Gly Ala Thr Leu LeuCys Leu Leu Leu Ala Ala 1 5 10 15 Ala Val Pro Thr Ala Pro Ala Pro AlaPro Thr Ala Thr Ser Ala 20 25 30 Pro Val Lys Pro Gly Pro Ala Leu Ser TyrPro Gln Glu Glu Ala 35 40 45 Thr Leu Asn Glu Met Phe Arg Glu Val Glu GluLeu Met Glu Asp 50 55 60 Thr Gln His Lys Leu Arg Ser Ala Val Glu Glu MetGlu Ala Glu 65 70 75 Glu Ala Ala Ala Lys Ala Ser Ser Glu Val Asn Leu AlaAsn Leu 80 85 90 Pro Pro Ser Tyr His Asn Glu Thr Asn Thr Asp Thr Lys ValGly 95 100 105 Asn Asn Thr Ile His Val His Arg Glu Ile His Lys Ile ThrAsn 110 115 120 Asn Gln Thr Gly Gln Met Val Phe Ser Glu Thr Val Ile ThrSer 125 130 135 Val Gly Asp Glu Glu Gly Arg Arg Ser His Glu Cys Ile IleAsp 140 145 150 Glu Asp Cys Gly Pro Ser Met Tyr Cys Gln Phe Ala Ser PheGln 155 160 165 Tyr Thr Cys Gln Pro Cys Arg Gly Gln Arg Met Leu Cys ThrArg 170 175 180 Asp Ser Glu Cys Cys Gly Asp Gln Leu Cys Val Trp Gly HisCys 185 190 195 Thr Lys Met Ala Thr Arg Gly Ser Asn Gly Thr Ile Cys AspAsn 200 205 210 Gln Arg Asp Cys Gln Pro Gly Leu Cys Cys Ala Phe Gln ArgGly 215 220 225 Leu Leu Phe Pro Val Cys Thr Pro Leu Pro Val Glu Gly GluLeu 230 235 240 Cys His Asp Pro Ala Ser Arg Leu Leu Asp Leu Ile Thr TrpGlu 245 250 255 Leu Glu Pro Asp Gly Ala Leu Asp Arg Cys Pro Cys Ala SerGly 260 265 270 Leu Leu Cys Gln Pro His Ser His Ser Leu Val Tyr Val CysLys 275 280 285 Pro Thr Phe Val Gly Ser Arg Asp Gln Asp Gly Glu Ile LeuLeu 290 295 300 Pro Arg Glu Val Pro Asp Glu Tyr Glu Val Gly Ser Phe MetGlu 305 310 315 Glu Val Arg Gln Glu Leu Glu Asp Leu Glu Arg Ser Leu ThrGlu 320 325 330 Glu Met Ala Leu Gly Glu Pro Ala Ala Ala Ala Ala Ala LeuLeu 335 340 345 Gly Gly Glu Glu Ile 350 9 1395 DNA Homo Sapien 9cggacgcgtg ggcggacgcg tgggggctgt gagaaagtgc caataaatac 50 atcatgcaaccccacggccc accttgtgaa ctcctcgtgc ccagggctga 100 tgtgcgtctt ccagggctactcatccaaag gcctaatcca acgttctgtc 150 ttcaatctgc aaatctatgg ggtcctggggctcttctgga cccttaactg 200 ggtactggcc ctgggccaat gcgtcctcgc tggagcctttgcctccttct 250 actgggcctt ccacaagccc caggacatcc ctaccttccc cttaatctct300 gccttcatcc gcacactccg ttaccacact gggtcattgg catttggagc 350cctcatcctg acccttgtgc agatagcccg ggtcatcttg gagtatattg 400 accacaagctcagaggagtg cagaaccctg tagcccgctg catcatgtgc 450 tgtttcaagt gctgcctctggtgtctggaa aaatttatca agttcctaaa 500 ccgcaatgca tacatcatga tcgccatctacgggaagaat ttctgtgtct 550 cagccaaaaa tgcgttcatg ctactcatgc gaaacattgtcagggtggtc 600 gtcctggaca aagtcacaga cctgctgctg ttctttggga agctgctggt650 ggtcggaggc gtgggggtcc tgtccttctt ttttttctcc ggtcgcatcc 700cggggctggg taaagacttt aagagccccc acctcaacta ttactggctg 750 cccatcatgacctccatcct gggggcctat gtcatcgcca gcggcttctt 800 cagcgttttc ggcatgtgtgtggacacgct cttcctctgc ttcctggaag 850 acctggagcg gaacaacggc tccctggaccggccctacta catgtccaag 900 agccttctaa agattctggg caagaagaac gaggcgcccccggacaacaa 950 gaagaggaag aagtgacagc tccggccctg atccaggact gcaccccacc1000 cccaccgtcc agccatccaa cctcacttcg ccttacaggt ctccattttg 1050tggtaaaaaa aggttttagg ccaggcgccg tggctcacgc ctgtaatcca 1100 acactttgagaggctgaggc gggcggatca cctgagtcag gagttcgaga 1150 ccagcctggc caacatggtgaaacctccgt ctctattaaa aatacaaaaa 1200 ttagccgaga gtggtggcat gcacctgtcatcccagctac tcgggaggct 1250 gaggcaggag aatcgcttga acccgggagg cagaggttgcagtgagccga 1300 gatcgcgcca ctgcactcca acctgggtga cagactctgt ctccaaaaca1350 aaacaaacaa acaaaaagat tttattaaag atattttgtt aactc 1395 10 321 PRTHomo Sapien 10 Arg Thr Arg Gly Arg Thr Arg Gly Gly Cys Glu Lys Val ProIle 1 5 10 15 Asn Thr Ser Cys Asn Pro Thr Ala His Leu Val Asn Ser SerCys 20 25 30 Pro Gly Leu Met Cys Val Phe Gln Gly Tyr Ser Ser Lys Gly Leu35 40 45 Ile Gln Arg Ser Val Phe Asn Leu Gln Ile Tyr Gly Val Leu Gly 5055 60 Leu Phe Trp Thr Leu Asn Trp Val Leu Ala Leu Gly Gln Cys Val 65 7075 Leu Ala Gly Ala Phe Ala Ser Phe Tyr Trp Ala Phe His Lys Pro 80 85 90Gln Asp Ile Pro Thr Phe Pro Leu Ile Ser Ala Phe Ile Arg Thr 95 100 105Leu Arg Tyr His Thr Gly Ser Leu Ala Phe Gly Ala Leu Ile Leu 110 115 120Thr Leu Val Gln Ile Ala Arg Val Ile Leu Glu Tyr Ile Asp His 125 130 135Lys Leu Arg Gly Val Gln Asn Pro Val Ala Arg Cys Ile Met Cys 140 145 150Cys Phe Lys Cys Cys Leu Trp Cys Leu Glu Lys Phe Ile Lys Phe 155 160 165Leu Asn Arg Asn Ala Tyr Ile Met Ile Ala Ile Tyr Gly Lys Asn 170 175 180Phe Cys Val Ser Ala Lys Asn Ala Phe Met Leu Leu Met Arg Asn 185 190 195Ile Val Arg Val Val Val Leu Asp Lys Val Thr Asp Leu Leu Leu 200 205 210Phe Phe Gly Lys Leu Leu Val Val Gly Gly Val Gly Val Leu Ser 215 220 225Phe Phe Phe Phe Ser Gly Arg Ile Pro Gly Leu Gly Lys Asp Phe 230 235 240Lys Ser Pro His Leu Asn Tyr Tyr Trp Leu Pro Ile Met Thr Ser 245 250 255Ile Leu Gly Ala Tyr Val Ile Ala Ser Gly Phe Phe Ser Val Phe 260 265 270Gly Met Cys Val Asp Thr Leu Phe Leu Cys Phe Leu Glu Asp Leu 275 280 285Glu Arg Asn Asn Gly Ser Leu Asp Arg Pro Tyr Tyr Met Ser Lys 290 295 300Ser Leu Leu Lys Ile Leu Gly Lys Lys Asn Glu Ala Pro Pro Asp 305 310 315Asn Lys Lys Arg Lys Lys 320 11 1901 DNA Homo Sapien 11 gccccgcgcccggcgccggg cgcccgaagc cgggagccac cgccatgggg 50 gcctgcctgg gagcctgctccctgctcagc tgcgcgtcct gcctctgcgg 100 ctctgccccc tgcatcctgt gcagctgctgccccgccagc cgcaactcca 150 ccgtgagccg cctcatcttc acgttcttcc tcttcctgggggtgctggtg 200 tccatcatta tgctgagccc gggcgtggag agtcagctct acaagctgcc250 ctgggtgtgt gaggaggggg ccgggatccc caccgtcctg cagggccaca 300tcgactgtgg ctccctgctt ggctaccgcg ctgtctaccg catgtgcttc 350 gccacggcggccttcttctt cttctttttc accctgctca tgctctgcgt 400 gagcagcagc cgggacccccgggctgccat ccagaatggg ttttggttct 450 ttaagttcct gatcctggtg ggcctcaccgtgggtgcctt ctacatccct 500 gacggctcct tcaccaacat ctggttctac ttcggcgtcgtgggctcctt 550 cctcttcatc ctcatccagc tggtgctgct catcgacttt gcgcactcct600 ggaaccagcg gtggctgggc aaggccgagg agtgcgattc ccgtgcctgg 650tacgcaggcc tcttcttctt cactctcctc ttctacttgc tgtcgatcgc 700 ggccgtggcgctgatgttca tgtactacac tgagcccagc ggctgccacg 750 agggcaaggt cttcatcagcctcaacctca ccttctgtgt ctgcgtgtcc 800 atcgctgctg tcctgcccaa ggtccaggacgcccagccca actcgggtct 850 gctgcaggcc tcggtcatca ccctctacac catgtttgtcacctggtcag 900 ccctatccag tatccctgaa cagaaatgca acccccattt gccaacccag950 ctgggcaacg agacagttgt ggcaggcccc gagggctatg agacccagtg 1000gtgggatgcc ccgagcattg tgggcctcat catcttcctc ctgtgcaccc 1050 tcttcatcagtctgcgctcc tcagaccacc ggcaggtgaa cagcctgatg 1100 cagaccgagg agtgcccacctatgctagac gccacacagc agcagcagca 1150 gcaggtggca gcctgtgagg gccgggcctttgacaacgag caggacggcg 1200 tcacctacag ctactccttc ttccacttct gcctggtgctggcctcactg 1250 cacgtcatga tgacgctcac caactggtac aagcccggtg agacccggaa1300 gatgatcagc acgtggaccg ccgtgtgggt gaagatctgt gccagctggg 1350cagggctgct cctctacctg tggaccctgg tagccccact cctcctgcgc 1400 aaccgcgacttcagctgagg cagcctcaca gcctgccatc tggtgcctcc 1450 tgccacctgg tgcctctcggctcggtgaca gccaacctgc cccctcccca 1500 caccaatcag ccaggctgag cccccacccctgccccagct ccaggacctg 1550 cccctgagcc gggccttcta gtcgtagtgc cttcagggtccgaggagcat 1600 caggctcctg cagagcccca tccccccgcc acacccacac ggtggagctg1650 cctcttcctt cccctcctcc ctgttgccca tactcagcat ctcggatgaa 1700agggctccct tgtcctcagg ctccacggga gcggggctgc tggagagagc 1750 ggggaactcccaccacagtg gggcatccgg cactgaagcc ctggtgttcc 1800 tggtcacgtc ccccaggggaccctgccccc ttcctggact tcgtgcctta 1850 ctgagtctct aagacttttt ctaataaacaagccagtgcg tgtaaaaaaa 1900 a 1901 12 457 PRT Homo Sapien 12 Met Gly AlaCys Leu Gly Ala Cys Ser Leu Leu Ser Cys Ala Ser 1 5 10 15 Cys Leu CysGly Ser Ala Pro Cys Ile Leu Cys Ser Cys Cys Pro 20 25 30 Ala Ser Arg AsnSer Thr Val Ser Arg Leu Ile Phe Thr Phe Phe 35 40 45 Leu Phe Leu Gly ValLeu Val Ser Ile Ile Met Leu Ser Pro Gly 50 55 60 Val Glu Ser Gln Leu TyrLys Leu Pro Trp Val Cys Glu Glu Gly 65 70 75 Ala Gly Ile Pro Thr Val LeuGln Gly His Ile Asp Cys Gly Ser 80 85 90 Leu Leu Gly Tyr Arg Ala Val TyrArg Met Cys Phe Ala Thr Ala 95 100 105 Ala Phe Phe Phe Phe Phe Phe ThrLeu Leu Met Leu Cys Val Ser 110 115 120 Ser Ser Arg Asp Pro Arg Ala AlaIle Gln Asn Gly Phe Trp Phe 125 130 135 Phe Lys Phe Leu Ile Leu Val GlyLeu Thr Val Gly Ala Phe Tyr 140 145 150 Ile Pro Asp Gly Ser Phe Thr AsnIle Trp Phe Tyr Phe Gly Val 155 160 165 Val Gly Ser Phe Leu Phe Ile LeuIle Gln Leu Val Leu Leu Ile 170 175 180 Asp Phe Ala His Ser Trp Asn GlnArg Trp Leu Gly Lys Ala Glu 185 190 195 Glu Cys Asp Ser Arg Ala Trp TyrAla Gly Leu Phe Phe Phe Thr 200 205 210 Leu Leu Phe Tyr Leu Leu Ser IleAla Ala Val Ala Leu Met Phe 215 220 225 Met Tyr Tyr Thr Glu Pro Ser GlyCys His Glu Gly Lys Val Phe 230 235 240 Ile Ser Leu Asn Leu Thr Phe CysVal Cys Val Ser Ile Ala Ala 245 250 255 Val Leu Pro Lys Val Gln Asp AlaGln Pro Asn Ser Gly Leu Leu 260 265 270 Gln Ala Ser Val Ile Thr Leu TyrThr Met Phe Val Thr Trp Ser 275 280 285 Ala Leu Ser Ser Ile Pro Glu GlnLys Cys Asn Pro His Leu Pro 290 295 300 Thr Gln Leu Gly Asn Glu Thr ValVal Ala Gly Pro Glu Gly Tyr 305 310 315 Glu Thr Gln Trp Trp Asp Ala ProSer Ile Val Gly Leu Ile Ile 320 325 330 Phe Leu Leu Cys Thr Leu Phe IleSer Leu Arg Ser Ser Asp His 335 340 345 Arg Gln Val Asn Ser Leu Met GlnThr Glu Glu Cys Pro Pro Met 350 355 360 Leu Asp Ala Thr Gln Gln Gln GlnGln Gln Val Ala Ala Cys Glu 365 370 375 Gly Arg Ala Phe Asp Asn Glu GlnAsp Gly Val Thr Tyr Ser Tyr 380 385 390 Ser Phe Phe His Phe Cys Leu ValLeu Ala Ser Leu His Val Met 395 400 405 Met Thr Leu Thr Asn Trp Tyr LysPro Gly Glu Thr Arg Lys Met 410 415 420 Ile Ser Thr Trp Thr Ala Val TrpVal Lys Ile Cys Ala Ser Trp 425 430 435 Ala Gly Leu Leu Leu Tyr Leu TrpThr Leu Val Ala Pro Leu Leu 440 445 450 Leu Arg Asn Arg Asp Phe Ser 45513 1572 DNA Homo Sapien 13 cgggccagcc tggggcggcc ggccaggaac cacccgttaaggtgtcttct 50 ctttagggat ggtgaggttg gaaaaagact cctgtaaccc tcctccagga 100tgaaccacct gccagaagac atggagaacg ctctcaccgg gagccagagc 150 tcccatgcttctctgcgcaa tatccattcc atcaacccca cacaactcat 200 ggccaggatt gagtcctatgaaggaaggga aaagaaaggc atatctgatg 250 tcaggaggac tttctgtttg tttgtcacctttgacctctt attcgtaaca 300 ttactgtgga taatagagtt aaatgtgaat ggaggcattgagaacacatt 350 agagaaggag gtgatgcagt atgactacta ttcttcatat tttgatatat400 ttcttctggc agtttttcga tttaaagtgt taatacttgc atatgctgtg 450tgcagactgc gccattggtg ggcaatagcg ttgacaacgg cagtgaccag 500 tgcctttttactagcaaaag tgatcctttc gaagcttttc tctcaagggg 550 cttttggcta tgtgctgcccatcatttcat tcatccttgc ctggattgag 600 acgtggttcc tggatttcaa agtgttacctcaagaagcag aagaagaaaa 650 cagactcctg atagttcagg atgcttcaga gagggcagcacttatacctg 700 gtggtctttc tgatggtcag ttttattccc ctcctgaatc cgaagcagga750 tctgaagaag ctgaagaaaa acaggacagt gagaaaccac ttttagaact 800atgagtacta cttttgttaa atgtgaaaaa ccctcacaga aagtcatcga 850 ggcaaaaagaggcaggcagt ggagtctccc tgtcgacagt aaagttgaaa 900 tggtgacgtc cactgctggctttattgaac agctaataaa gatttattta 950 ttgtaatacc tcacaaacgt tgtaccatatccatgcacat ttagttgcct 1000 gcctgtggct ggtaaggtaa tgtcatgatt catcctctcttcagtgagac 1050 tgagcctgat gtgttaacaa ataggtgaag aaagtcttgt gctgtattcc1100 taatcaaaag acttaatata ttgaagtaac acttttttag taagcaagat 1150acctttttat ttcaattcac agaatggaat ttttttgttt catgtctcag 1200 atttattttgtatttctttt ttaacactct acatttccct tgttttttaa 1250 ctcatgcaca tgtgctctttgtacagtttt aaaaagtgta ataaaatctg 1300 acatgtcaat gtggctagtt ttatttttcttgttttgcat tatgtgtatg 1350 gcctgaagtg ttggacttgc aaaaggggaa gaaaggaattgcgaatacat 1400 gtaaaatgtc accagacatt tgtattattt ttatcatgaa atcatgtttt1450 tctctgattg ttctgaaatg ttctaaatac tcttattttg aatgcacaaa 1500atgacttaaa ccattcatat catgtttcct ttgcgttcag ccaatttcaa 1550 ttaaaatgaactaaattaaa aa 1572 14 234 PRT Homo Sapien 14 Met Asn His Leu Pro Glu AspMet Glu Asn Ala Leu Thr Gly Ser 1 5 10 15 Gln Ser Ser His Ala Ser LeuArg Asn Ile His Ser Ile Asn Pro 20 25 30 Thr Gln Leu Met Ala Arg Ile GluSer Tyr Glu Gly Arg Glu Lys 35 40 45 Lys Gly Ile Ser Asp Val Arg Arg ThrPhe Cys Leu Phe Val Thr 50 55 60 Phe Asp Leu Leu Phe Val Thr Leu Leu TrpIle Ile Glu Leu Asn 65 70 75 Val Asn Gly Gly Ile Glu Asn Thr Leu Glu LysGlu Val Met Gln 80 85 90 Tyr Asp Tyr Tyr Ser Ser Tyr Phe Asp Ile Phe LeuLeu Ala Val 95 100 105 Phe Arg Phe Lys Val Leu Ile Leu Ala Tyr Ala ValCys Arg Leu 110 115 120 Arg His Trp Trp Ala Ile Ala Leu Thr Thr Ala ValThr Ser Ala 125 130 135 Phe Leu Leu Ala Lys Val Ile Leu Ser Lys Leu PheSer Gln Gly 140 145 150 Ala Phe Gly Tyr Val Leu Pro Ile Ile Ser Phe IleLeu Ala Trp 155 160 165 Ile Glu Thr Trp Phe Leu Asp Phe Lys Val Leu ProGln Glu Ala 170 175 180 Glu Glu Glu Asn Arg Leu Leu Ile Val Gln Asp AlaSer Glu Arg 185 190 195 Ala Ala Leu Ile Pro Gly Gly Leu Ser Asp Gly GlnPhe Tyr Ser 200 205 210 Pro Pro Glu Ser Glu Ala Gly Ser Glu Glu Ala GluGlu Lys Gln 215 220 225 Asp Ser Glu Lys Pro Leu Leu Glu Leu 230 15 2768DNA Homo Sapien 15 actcgaacgc agttgcttcg ggacccagga ccccctcgggcccgacccgc 50 caggaaagac tgaggccgcg gcctgccccg cccggctccc tgcgccgccg 100ccgcctcccg ggacagaaga tgtgctccag ggtccctctg ctgctgccgc 150 tgctcctgctactggccctg gggcctgggg tgcagggctg cccatccggc 200 tgccagtgca gccagccacagacagtcttc tgcactgccc gccaggggac 250 cacggtgccc cgagacgtgc cacccgacacggtggggctg tacgtctttg 300 agaacggcat caccatgctc gacgcaggca gctttgccggcctgccgggc 350 ctgcagctcc tggacctgtc acagaaccag atcgccagcc tgcccagcgg400 ggtcttccag ccactcgcca acctcagcaa cctggacctg acggccaaca 450ggctgcatga aatcaccaat gagaccttcc gtggcctgcg gcgcctcgag 500 cgcctctacctgggcaagaa ccgcatccgc cacatccagc ctggtgcctt 550 cgacacgctc gaccgcctcctggagctcaa gctgcaggac aacgagctgc 600 gggcactgcc cccgctgcgc ctgccccgcctgctgctgct ggacctcagc 650 cacaacagcc tcctggccct ggagcccggc atcctggacactgccaacgt 700 ggaggcgctg cggctggctg gtctggggct gcagcagctg gacgaggggc750 tcttcagccg cttgcgcaac ctccacgacc tggatgtgtc cgacaaccag 800ctggagcgag tgccacctgt gatccgaggc ctccggggcc tgacgcgcct 850 gcggctggccggcaacaccc gcattgccca gctgcggccc gaggacctgg 900 ccggcctggc tgccctgcaggagctggatg tgagcaacct aagcctgcag 950 gccctgcctg gcgacctctc gggcctcttcccccgcctgc ggctgctggc 1000 agctgcccgc aaccccttca actgcgtgtg ccccctgagctggtttggcc 1050 cctgggtgcg cgagagccac gtcacactgg ccagccctga ggagacgcgc1100 tgccacttcc cgcccaagaa cgctggccgg ctgctcctgg agcttgacta 1150cgccgacttt ggctgcccag ccaccaccac cacagccaca gtgcccacca 1200 cgaggcccgtggtgcgggag cccacagcct tgtcttctag cttggctcct 1250 acctggctta gccccacagcgccggccact gaggccccca gcccgccctc 1300 cactgcccca ccgactgtag ggcctgtcccccagccccag gactgcccac 1350 cgtccacctg cctcaatggg ggcacatgcc acctggggacacggcaccac 1400 ctggcgtgct tgtgccccga aggcttcacg ggcctgtact gtgagagcca1450 gatggggcag gggacacggc ccagccctac accagtcacg ccgaggccac 1500cacggtccct gaccctgggc atcgagccgg tgagccccac ctccctgcgc 1550 gtggggctgcagcgctacct ccaggggagc tccgtgcagc tcaggagcct 1600 ccgtctcacc tatcgcaacctatcgggccc tgataagcgg ctggtgacgc 1650 tgcgactgcc tgcctcgctc gctgagtacacggtcaccca gctgcggccc 1700 aacgccactt actccgtctg tgtcatgcct ttggggcccgggcgggtgcc 1750 ggagggcgag gaggcctgcg gggaggccca tacaccccca gccgtccact1800 ccaaccacgc cccagtcacc caggcccgcg agggcaacct gccgctcctc 1850attgcgcccg ccctggccgc ggtgctcctg gccgcgctgg ctgcggtggg 1900 ggcagcctactgtgtgcggc gggggcgggc catggcagca gcggctcagg 1950 acaaagggca ggtggggccaggggctgggc ccctggaact ggagggagtg 2000 aaggtcccct tggagccagg cccgaaggcaacagagggcg gtggagaggc 2050 cctgcccagc gggtctgagt gtgaggtgcc actcatgggcttcccagggc 2100 ctggcctcca gtcacccctc cacgcaaagc cctacatcta agccagagag2150 agacagggca gctggggccg ggctctcagc cagtgagatg gccagccccc 2200tcctgctgcc acaccacgta agttctcagt cccaacctcg gggatgtgtg 2250 cagacagggctgtgtgacca cagctgggcc ctgttccctc tggacctcgg 2300 tctcctcatc tgtgagatgctgtggcccag ctgacgagcc ctaacgtccc 2350 cagaaccgag tgcctatgag gacagtgtccgccctgccct ccgcaacgtg 2400 cagtccctgg gcacggcggg ccctgccatg tgctggtaacgcatgcctgg 2450 gtcctgctgg gctctcccac tccaggcgga ccctgggggc cagtgaagga2500 agctcccgga aagagcagag ggagagcggg taggcggctg tgtgactcta 2550gtcttggccc caggaagcga aggaacaaaa gaaactggaa aggaagatgc 2600 tttaggaacatgttttgctt ttttaaaata tatatattta taagagatcc 2650 tttcccattt attctgggaagatgtttttc aaactcagag acaaggactt 2700 tggtttttgt aagacaaacg atgatatgaaggccttttgt aagaaaaaat 2750 aaaagatgaa gtgtgaaa 2768 16 673 PRT HomoSapien 16 Met Cys Ser Arg Val Pro Leu Leu Leu Pro Leu Leu Leu Leu Leu 15 10 15 Ala Leu Gly Pro Gly Val Gln Gly Cys Pro Ser Gly Cys Gln Cys 2025 30 Ser Gln Pro Gln Thr Val Phe Cys Thr Ala Arg Gln Gly Thr Thr 35 4045 Val Pro Arg Asp Val Pro Pro Asp Thr Val Gly Leu Tyr Val Phe 50 55 60Glu Asn Gly Ile Thr Met Leu Asp Ala Gly Ser Phe Ala Gly Leu 65 70 75 ProGly Leu Gln Leu Leu Asp Leu Ser Gln Asn Gln Ile Ala Ser 80 85 90 Leu ProSer Gly Val Phe Gln Pro Leu Ala Asn Leu Ser Asn Leu 95 100 105 Asp LeuThr Ala Asn Arg Leu His Glu Ile Thr Asn Glu Thr Phe 110 115 120 Arg GlyLeu Arg Arg Leu Glu Arg Leu Tyr Leu Gly Lys Asn Arg 125 130 135 Ile ArgHis Ile Gln Pro Gly Ala Phe Asp Thr Leu Asp Arg Leu 140 145 150 Leu GluLeu Lys Leu Gln Asp Asn Glu Leu Arg Ala Leu Pro Pro 155 160 165 Leu ArgLeu Pro Arg Leu Leu Leu Leu Asp Leu Ser His Asn Ser 170 175 180 Leu LeuAla Leu Glu Pro Gly Ile Leu Asp Thr Ala Asn Val Glu 185 190 195 Ala LeuArg Leu Ala Gly Leu Gly Leu Gln Gln Leu Asp Glu Gly 200 205 210 Leu PheSer Arg Leu Arg Asn Leu His Asp Leu Asp Val Ser Asp 215 220 225 Asn GlnLeu Glu Arg Val Pro Pro Val Ile Arg Gly Leu Arg Gly 230 235 240 Leu ThrArg Leu Arg Leu Ala Gly Asn Thr Arg Ile Ala Gln Leu 245 250 255 Arg ProGlu Asp Leu Ala Gly Leu Ala Ala Leu Gln Glu Leu Asp 260 265 270 Val SerAsn Leu Ser Leu Gln Ala Leu Pro Gly Asp Leu Ser Gly 275 280 285 Leu PhePro Arg Leu Arg Leu Leu Ala Ala Ala Arg Asn Pro Phe 290 295 300 Asn CysVal Cys Pro Leu Ser Trp Phe Gly Pro Trp Val Arg Glu 305 310 315 Ser HisVal Thr Leu Ala Ser Pro Glu Glu Thr Arg Cys His Phe 320 325 330 Pro ProLys Asn Ala Gly Arg Leu Leu Leu Glu Leu Asp Tyr Ala 335 340 345 Asp PheGly Cys Pro Ala Thr Thr Thr Thr Ala Thr Val Pro Thr 350 355 360 Thr ArgPro Val Val Arg Glu Pro Thr Ala Leu Ser Ser Ser Leu 365 370 375 Ala ProThr Trp Leu Ser Pro Thr Ala Pro Ala Thr Glu Ala Pro 380 385 390 Ser ProPro Ser Thr Ala Pro Pro Thr Val Gly Pro Val Pro Gln 395 400 405 Pro GlnAsp Cys Pro Pro Ser Thr Cys Leu Asn Gly Gly Thr Cys 410 415 420 His LeuGly Thr Arg His His Leu Ala Cys Leu Cys Pro Glu Gly 425 430 435 Phe ThrGly Leu Tyr Cys Glu Ser Gln Met Gly Gln Gly Thr Arg 440 445 450 Pro SerPro Thr Pro Val Thr Pro Arg Pro Pro Arg Ser Leu Thr 455 460 465 Leu GlyIle Glu Pro Val Ser Pro Thr Ser Leu Arg Val Gly Leu 470 475 480 Gln ArgTyr Leu Gln Gly Ser Ser Val Gln Leu Arg Ser Leu Arg 485 490 495 Leu ThrTyr Arg Asn Leu Ser Gly Pro Asp Lys Arg Leu Val Thr 500 505 510 Leu ArgLeu Pro Ala Ser Leu Ala Glu Tyr Thr Val Thr Gln Leu 515 520 525 Arg ProAsn Ala Thr Tyr Ser Val Cys Val Met Pro Leu Gly Pro 530 535 540 Gly ArgVal Pro Glu Gly Glu Glu Ala Cys Gly Glu Ala His Thr 545 550 555 Pro ProAla Val His Ser Asn His Ala Pro Val Thr Gln Ala Arg 560 565 570 Glu GlyAsn Leu Pro Leu Leu Ile Ala Pro Ala Leu Ala Ala Val 575 580 585 Leu LeuAla Ala Leu Ala Ala Val Gly Ala Ala Tyr Cys Val Arg 590 595 600 Arg GlyArg Ala Met Ala Ala Ala Ala Gln Asp Lys Gly Gln Val 605 610 615 Gly ProGly Ala Gly Pro Leu Glu Leu Glu Gly Val Lys Val Pro 620 625 630 Leu GluPro Gly Pro Lys Ala Thr Glu Gly Gly Gly Glu Ala Leu 635 640 645 Pro SerGly Ser Glu Cys Glu Val Pro Leu Met Gly Phe Pro Gly 650 655 660 Pro GlyLeu Gln Ser Pro Leu His Ala Lys Pro Tyr Ile 665 670 17 1672 DNA HomoSapien 17 gcagcggcga ggcggcggtg gtggctgagt ccgtggtggc agaggcgaag 50gcgacagctc atgcgggtcc ggatagggct gacgctgctg ctgtgtgcgg 100 tgctgctgagcttggcctcg gcgtcctcgg atgaagaagg cagccaggat 150 gaatccttag attccaagactactttgaca tcagatgagt cagtaaagga 200 ccatactact gcaggcagag tagttgctggtcaaatattt cttgattcag 250 aagaatctga attagaatcc tctattcaag aagaggaagacagcctcaag 300 agccaagagg gggaaagtgt cacagaagat atcagctttc tagagtctcc350 aaatccagaa aacaaggact atgaagagcc aaagaaagta cggaaaccag 400ctttgaccgc cattgaaggc acagcacatg gggagccctg ccacttccct 450 tttcttttcctagataagga gtatgatgaa tgtacatcag atgggaggga 500 agatggcaga ctgtggtgtgctacaaccta tgactacaaa gcagatgaaa 550 agtggggctt ttgtgaaact gaagaagaggctgctaagag acggcagatg 600 caggaagcag aaatgatgta tcaaactgga atgaaaatccttaatggaag 650 caataagaaa agccaaaaaa gagaagcata tcggtatctc caaaaggcag700 caagcatgaa ccataccaaa gccctggaga gagtgtcata tgctctttta 750tttggtgatt acttgccaca gaatatccag gcagcgagag agatgtttga 800 gaagctgactgaggaaggct ctcccaaggg acagactgct cttggctttc 850 tgtatgcctc tggacttggtgttaattcaa gtcaggcaaa ggctcttgta 900 tattatacat ttggagctct tgggggcaatctaatagccc acatggtttt 950 ggtaagtaga ctttagtgga aggctaataa tattaacatcagaagaattt 1000 gtggtttata gcggccacaa ctttttcagc tttcatgatc cagatttgct1050 tgtattaaga ccaaatattc agttgaactt ccttcaaatt cttgttaatg 1100gatataacac atggaatcta catgtaaatg aaagttggtg gagtccacaa 1150 tttttctttaaaatgattag tttggctgat tgcccctaaa aagagagatc 1200 tgataaatgg ctctttttaaattttctctg agttggaatt gtcagaatca 1250 ttttttacat tagattatca taattttaaaaatttttctt tagtttttca 1300 aaattttgta aatggtggct atagaaaaac aacatgaaatattatacaat 1350 attttgcaac aatgccctaa gaattgttaa aattcatgga gttatttgtg1400 cagaatgact ccagagagct ctactttctg ttttttactt ttcatgattg 1450gctgtcttcc catttattct ggtcatttat tgctagtgac actgtgcctg 1500 cttccagtagtctcattttc cctattttgc taatttgtta ctttttcttt 1550 gctaatttgg aagattaactcatttttaat aaaattatgt ctaagattaa 1600 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaaaaaaaaaaaa aaaaaaaaaa 1650 aaaaaaaaaa aaaaaaaaaa aa 1672 18 301 PRT HomoSapien 18 Met Arg Val Arg Ile Gly Leu Thr Leu Leu Leu Cys Ala Val Leu 15 10 15 Leu Ser Leu Ala Ser Ala Ser Ser Asp Glu Glu Gly Ser Gln Asp 2025 30 Glu Ser Leu Asp Ser Lys Thr Thr Leu Thr Ser Asp Glu Ser Val 35 4045 Lys Asp His Thr Thr Ala Gly Arg Val Val Ala Gly Gln Ile Phe 50 55 60Leu Asp Ser Glu Glu Ser Glu Leu Glu Ser Ser Ile Gln Glu Glu 65 70 75 GluAsp Ser Leu Lys Ser Gln Glu Gly Glu Ser Val Thr Glu Asp 80 85 90 Ile SerPhe Leu Glu Ser Pro Asn Pro Glu Asn Lys Asp Tyr Glu 95 100 105 Glu ProLys Lys Val Arg Lys Pro Ala Leu Thr Ala Ile Glu Gly 110 115 120 Thr AlaHis Gly Glu Pro Cys His Phe Pro Phe Leu Phe Leu Asp 125 130 135 Lys GluTyr Asp Glu Cys Thr Ser Asp Gly Arg Glu Asp Gly Arg 140 145 150 Leu TrpCys Ala Thr Thr Tyr Asp Tyr Lys Ala Asp Glu Lys Trp 155 160 165 Gly PheCys Glu Thr Glu Glu Glu Ala Ala Lys Arg Arg Gln Met 170 175 180 Gln GluAla Glu Met Met Tyr Gln Thr Gly Met Lys Ile Leu Asn 185 190 195 Gly SerAsn Lys Lys Ser Gln Lys Arg Glu Ala Tyr Arg Tyr Leu 200 205 210 Gln LysAla Ala Ser Met Asn His Thr Lys Ala Leu Glu Arg Val 215 220 225 Ser TyrAla Leu Leu Phe Gly Asp Tyr Leu Pro Gln Asn Ile Gln 230 235 240 Ala AlaArg Glu Met Phe Glu Lys Leu Thr Glu Glu Gly Ser Pro 245 250 255 Lys GlyGln Thr Ala Leu Gly Phe Leu Tyr Ala Ser Gly Leu Gly 260 265 270 Val AsnSer Ser Gln Ala Lys Ala Leu Val Tyr Tyr Thr Phe Gly 275 280 285 Ala LeuGly Gly Asn Leu Ile Ala His Met Val Leu Val Ser Arg 290 295 300 Leu 191508 DNA Homo Sapien 19 aattcagatt ttaagcccat tctgcagtgg aatttcatgaactagcaaga 50 ggacaccatc ttcttgtatt atacaagaaa ggagtgtacc tatcacacac 100agggggaaaa atgctctttt gggtgctagg cctcctaatc ctctgtggtt 150 ttctgtggactcgtaaagga aaactaaaga ttgaagacat cactgataag 200 tacattttta tcactggatgtgactcgggc tttggaaact tggcagccag 250 aacttttgat aaaaagggat ttcatgtaatcgctgcctgt ctgactgaat 300 caggatcaac agctttaaag gcagaaacct cagagagacttcgtactgtg 350 cttctggatg tgaccgaccc agagaatgtc aagaggactg cccagtgggt400 gaagaaccaa gttggggaga aaggtctctg gggtctgatc aataatgctg 450gtgttcccgg cgtgctggct cccactgact ggctgacact agaggactac 500 agagaacctattgaagtgaa cctgtttgga ctcatcagtg tgacactaaa 550 tatgcttcct ttggtcaagaaagctcaagg gagagttatt aatgtctcca 600 gtgttggagg tcgccttgca atcgttggagggggctatac tccatccaaa 650 tatgcagtgg aaggtttcaa tgacagctta agacgggacatgaaagcttt 700 tggtgtgcac gtctcatgca ttgaaccagg attgttcaaa acaaacttgg750 cagatccagt aaaggtaatt gaaaaaaaac tcgccatttg ggagcagctg 800tctccagaca tcaaacaaca atatggagaa ggttacattg aaaaaagtct 850 agacaaactgaaaggcaata aatcctatgt gaacatggac ctctctccgg 900 tggtagagtg catggaccacgctctaacaa gtctcttccc taagactcat 950 tatgccgctg gaaaagatgc caaaattttctggatacctc tgtctcacat 1000 gccagcagct ttgcaagact ttttattgtt gaaacagaaagcagagctgg 1050 ctaatcccaa ggcagtgtga ctcagctaac cacaaatgtc tcctccaggc1100 tatgaaattg gccgatttca agaacacatc tccttttcaa ccccattcct 1150tatctgctcc aacctggact catttagatc gtgcttattt ggattgcaaa 1200 agggagtcccaccatcgctg gtggtatccc agggtccctg ctcaagtttt 1250 ctttgaaaag gagggctggaatggtacatc acataggcaa gtcctgccct 1300 gtatttaggc tttgcctgct tggtgtgatgtaagggaaat tgaaagactt 1350 gcccattcaa aatgatcttt accgtggcct gccccatgcttatggtcccc 1400 agcatttaca gtaacttgtg aatgttaagt atcatctctt atctaaatat1450 taaaagataa gtcaacccaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 1500aaaaaaaa 1508 20 319 PRT Homo Sapien 20 Met Leu Phe Trp Val Leu Gly LeuLeu Ile Leu Cys Gly Phe Leu 1 5 10 15 Trp Thr Arg Lys Gly Lys Leu LysIle Glu Asp Ile Thr Asp Lys 20 25 30 Tyr Ile Phe Ile Thr Gly Cys Asp SerGly Phe Gly Asn Leu Ala 35 40 45 Ala Arg Thr Phe Asp Lys Lys Gly Phe HisVal Ile Ala Ala Cys 50 55 60 Leu Thr Glu Ser Gly Ser Thr Ala Leu Lys AlaGlu Thr Ser Glu 65 70 75 Arg Leu Arg Thr Val Leu Leu Asp Val Thr Asp ProGlu Asn Val 80 85 90 Lys Arg Thr Ala Gln Trp Val Lys Asn Gln Val Gly GluLys Gly 95 100 105 Leu Trp Gly Leu Ile Asn Asn Ala Gly Val Pro Gly ValLeu Ala 110 115 120 Pro Thr Asp Trp Leu Thr Leu Glu Asp Tyr Arg Glu ProIle Glu 125 130 135 Val Asn Leu Phe Gly Leu Ile Ser Val Thr Leu Asn MetLeu Pro 140 145 150 Leu Val Lys Lys Ala Gln Gly Arg Val Ile Asn Val SerSer Val 155 160 165 Gly Gly Arg Leu Ala Ile Val Gly Gly Gly Tyr Thr ProSer Lys 170 175 180 Tyr Ala Val Glu Gly Phe Asn Asp Ser Leu Arg Arg AspMet Lys 185 190 195 Ala Phe Gly Val His Val Ser Cys Ile Glu Pro Gly LeuPhe Lys 200 205 210 Thr Asn Leu Ala Asp Pro Val Lys Val Ile Glu Lys LysLeu Ala 215 220 225 Ile Trp Glu Gln Leu Ser Pro Asp Ile Lys Gln Gln TyrGly Glu 230 235 240 Gly Tyr Ile Glu Lys Ser Leu Asp Lys Leu Lys Gly AsnLys Ser 245 250 255 Tyr Val Asn Met Asp Leu Ser Pro Val Val Glu Cys MetAsp His 260 265 270 Ala Leu Thr Ser Leu Phe Pro Lys Thr His Tyr Ala AlaGly Lys 275 280 285 Asp Ala Lys Ile Phe Trp Ile Pro Leu Ser His Met ProAla Ala 290 295 300 Leu Gln Asp Phe Leu Leu Leu Lys Gln Lys Ala Glu LeuAla Asn 305 310 315 Pro Lys Ala Val 21 1849 DNA Homo Sapien 21ctgaggcggc ggtagcatgg agggggagag tacgtcggcg gtgctctcgg 50 gctttgtgctcggcgcactc gctttccagc acctcaacac ggactcggac 100 acggaaggtt ttcttcttggggaagtaaaa ggtgaagcca agaacagcat 150 tactgattcc caaatggatg atgttgaagttgtttataca attgacattc 200 agaaatatat tccatgctat cagcttttta gcttttataattcttcaggc 250 gaagtaaatg agcaagcact gaagaaaata ttatcaaatg tcaaaaagaa300 tgtggtaggt tggtacaaat tccgtcgtca ttcagatcag atcatgacgt 350ttagagagag gctgcttcac aaaaacttgc aggagcattt ttcaaaccaa 400 gaccttgtttttctgctatt aacaccaagt ataataacag aaagctgctc 450 tactcatcga ctggaacattccttatataa acctcaaaaa ggactttttc 500 acagggtacc tttagtggtt gccaatctgggcatgtctga acaactgggt 550 tataaaactg tatcaggttc ctgtatgtcc actggttttagccgagcagt 600 acaaacacac agctctaaat tttttgaaga agatggatcc ttaaaggagg650 tacataagat aaatgaaatg tatgcttcat tacaagagga attaaagagt 700atatgcaaaa aagtggaaga cagtgaacaa gcagtagata aactagtaaa 750 ggatgtaaacagattaaaac gagaaattga gaaaaggaga ggagcacaga 800 ttcaggcagc aagagagaagaacatccaaa aagaccctca ggagaacatt 850 tttctttgtc aggcattacg gaccttttttccaaattctg aatttcttca 900 ttcatgtgtt atgtctttaa aaaatagaca tgtttctaaaagtagctgta 950 actacaacca ccatctcgat gtagtagaca atctgacctt aatggtagaa1000 cacactgaca ttcctgaagc tagtccagct agtacaccac aaatcattaa 1050gcataaagcc ttagacttag atgacagatg gcaattcaag agatctcggt 1100 tgttagatacacaagacaaa cgatctaaag caaatactgg tagtagtaac 1150 caagataaag catccaaaatgagcagccca gaaacagatg aagaaattga 1200 aaagatgaag ggttttggtg aatattcacggtctcctaca ttttgatcct 1250 tttaacctta caaggagatt tttttatttg gctgatgggtaaagccaaac 1300 atttctattg tttttactat gttgagctac ttgcagtaag ttcatttgtt1350 tttactatgt tcacctgttt gcagtaatac acagataact cttagtgcat 1400ttacttcaca aagtactttt tcaaacatca gatgctttta tttccaaacc 1450 tttttttcacctttcactaa gttgttgagg ggaaggctta cacagacaca 1500 ttctttagaa ttggaaaagtgagaccaggc acagtggctc acacctgtaa 1550 tcccagcact tagggaagac aagtcaggaggattgattga agctaggagt 1600 tagagaccag cctgggcaac gtattgagac catgtctattaaaaaataaa 1650 atggaaaagc aagaatagcc ttattttcaa aatatggaaa gaaatttata1700 tgaaaattta tctgagtcat taaaattctc cttaagtgat acttttttag 1750aagtacatta tggctagagt tgccagataa aatgctggat atcatgcaat 1800 aaatttgcaaaacatcatct aaaatttaaa aaaaaaaaaa aaaaaaaaa 1849 22 409 PRT Homo Sapien22 Met Glu Gly Glu Ser Thr Ser Ala Val Leu Ser Gly Phe Val Leu 1 5 10 15Gly Ala Leu Ala Phe Gln His Leu Asn Thr Asp Ser Asp Thr Glu 20 25 30 GlyPhe Leu Leu Gly Glu Val Lys Gly Glu Ala Lys Asn Ser Ile 35 40 45 Thr AspSer Gln Met Asp Asp Val Glu Val Val Tyr Thr Ile Asp 50 55 60 Ile Gln LysTyr Ile Pro Cys Tyr Gln Leu Phe Ser Phe Tyr Asn 65 70 75 Ser Ser Gly GluVal Asn Glu Gln Ala Leu Lys Lys Ile Leu Ser 80 85 90 Asn Val Lys Lys AsnVal Val Gly Trp Tyr Lys Phe Arg Arg His 95 100 105 Ser Asp Gln Ile MetThr Phe Arg Glu Arg Leu Leu His Lys Asn 110 115 120 Leu Gln Glu His PheSer Asn Gln Asp Leu Val Phe Leu Leu Leu 125 130 135 Thr Pro Ser Ile IleThr Glu Ser Cys Ser Thr His Arg Leu Glu 140 145 150 His Ser Leu Tyr LysPro Gln Lys Gly Leu Phe His Arg Val Pro 155 160 165 Leu Val Val Ala AsnLeu Gly Met Ser Glu Gln Leu Gly Tyr Lys 170 175 180 Thr Val Ser Gly SerCys Met Ser Thr Gly Phe Ser Arg Ala Val 185 190 195 Gln Thr His Ser SerLys Phe Phe Glu Glu Asp Gly Ser Leu Lys 200 205 210 Glu Val His Lys IleAsn Glu Met Tyr Ala Ser Leu Gln Glu Glu 215 220 225 Leu Lys Ser Ile CysLys Lys Val Glu Asp Ser Glu Gln Ala Val 230 235 240 Asp Lys Leu Val LysAsp Val Asn Arg Leu Lys Arg Glu Ile Glu 245 250 255 Lys Arg Arg Gly AlaGln Ile Gln Ala Ala Arg Glu Lys Asn Ile 260 265 270 Gln Lys Asp Pro GlnGlu Asn Ile Phe Leu Cys Gln Ala Leu Arg 275 280 285 Thr Phe Phe Pro AsnSer Glu Phe Leu His Ser Cys Val Met Ser 290 295 300 Leu Lys Asn Arg HisVal Ser Lys Ser Ser Cys Asn Tyr Asn His 305 310 315 His Leu Asp Val ValAsp Asn Leu Thr Leu Met Val Glu His Thr 320 325 330 Asp Ile Pro Glu AlaSer Pro Ala Ser Thr Pro Gln Ile Ile Lys 335 340 345 His Lys Ala Leu AspLeu Asp Asp Arg Trp Gln Phe Lys Arg Ser 350 355 360 Arg Leu Leu Asp ThrGln Asp Lys Arg Ser Lys Ala Asn Thr Gly 365 370 375 Ser Ser Asn Gln AspLys Ala Ser Lys Met Ser Ser Pro Glu Thr 380 385 390 Asp Glu Glu Ile GluLys Met Lys Gly Phe Gly Glu Tyr Ser Arg 395 400 405 Ser Pro Thr Phe 232651 DNA Homo Sapien 23 ggcacagccg cgcggcggag ggcagagtca gccgagccgagtccagccgg 50 acgagcggac cagcgcaggg cagcccaagc agcgcgcagc gaacgcccgc 100cgccgcccac accctctgcg gtccccgcgg cgcctgccac ccttccctcc 150 ttccccgcgtccccgcctcg ccggccagtc agcttgccgg gttcgctgcc 200 ccgcgaaacc ccgaggtcaccagcccgcgc ctctgcttcc ctgggccgcg 250 cgccgcctcc acgccctcct tctcccctggcccggcgcct ggcaccgggg 300 accgttgcct gacgcgaggc ccagctctac ttttcgccccgcgtctcctc 350 cgcctgctcg cctcttccac caactccaac tccttctccc tccagctcca400 ctcgctagtc cccgactccg ccagccctcg gcccgctgcc gtagcgccgc 450ttcccgtccg gtcccaaagg tgggaacgcg tccgccccgg cccgcaccat 500 ggcacggttcggcttgcccg cgcttctctg caccctggca gtgctcagcg 550 ccgcgctgct ggctgccgagctcaagtcga aaagttgctc ggaagtgcga 600 cgtctttacg tgtccaaagg cttcaacaagaacgatgccc ccctccacga 650 gatcaacggt gatcatttga agatctgtcc ccagggttctacctgctgct 700 ctcaagagat ggaggagaag tacagcctgc aaagtaaaga tgatttcaaa750 agtgtggtca gcgaacagtg caatcatttg caagctgtct ttgcttcacg 800ttacaagaag tttgatgaat tcttcaaaga actacttgaa aatgcagaga 850 aatccctgaatgatatgttt gtgaagacat atggccattt atacatgcaa 900 aattctgagc tatttaaagatctcttcgta gagttgaaac gttactacgt 950 ggtgggaaat gtgaacctgg aagaaatgctaaatgacttc tgggctcgcc 1000 tcctggagcg gatgttccgc ctggtgaact cccagtaccactttacagat 1050 gagtatctgg aatgtgtgag caagtatacg gagcagctga agcccttcgg1100 agatgtccct cgcaaattga agctccaggt tactcgtgct tttgtagcag 1150cccgtacttt cgctcaaggc ttagcggttg cgggagatgt cgtgagcaag 1200 gtctccgtggtaaaccccac agcccagtgt acccatgccc tgttgaagat 1250 gatctactgc tcccactgccggggtctcgt gactgtgaag ccatgttaca 1300 actactgctc aaacatcatg agaggctgtttggccaacca aggggatctc 1350 gattttgaat ggaacaattt catagatgct atgctgatggtggcagagag 1400 gctagagggt cctttcaaca ttgaatcggt catggatccc atcgatgtga1450 agatttctga tgctattatg aacatgcagg ataatagtgt tcaagtgtct 1500cagaaggttt tccagggatg tggacccccc aagcccctcc cagctggacg 1550 aatttctcgttccatctctg aaagtgcctt cagtgctcgc ttcagaccac 1600 atcaccccga ggaacgcccaaccacagcag ctggcactag tttggaccga 1650 ctggttactg atgtcaagga gaaactgaaacaggccaaga aattctggtc 1700 ctcccttccg agcaacgttt gcaacgatga gaggatggctgcaggaaacg 1750 gcaatgagga tgactgttgg aatgggaaag gcaaaagcag gtacctgttt1800 gcagtgacag gaaatggatt agccaaccag ggcaacaacc cagaggtcca 1850ggttgacacc agcaaaccag acatactgat ccttcgtcaa atcatggctc 1900 ttcgagtgatgaccagcaag atgaagaatg catacaatgg gaacgacgtg 1950 gacttctttg atatcagtgatgaaagtagt ggagaaggaa gtggaagtgg 2000 ctgtgagtat cagcagtgcc cttcagagtttgactacaat gccactgacc 2050 atgctgggaa gagtgccaat gagaaagccg acagtgctggtgtccgtcct 2100 ggggcacagg cctacctcct cactgtcttc tgcatcttgt tcctggttat2150 gcagagagag tggagataat tctcaaactc tgagaaaaag tgttcatcaa 2200aaagttaaaa ggcaccagtt atcacttttc taccatccta gtgactttgc 2250 tttttaaatgaatggacaac aatgtacagt ttttactatg tggccactgg 2300 tttaagaagt gctgactttgttttctcatt cagttttggg aggaaaaggg 2350 actgtgcatt gagttggttc ctgctcccccaaaccatgtt aaacgtggct 2400 aacagtgtag gtacagaact atagttagtt gtgcatttgtgattttatca 2450 ctctattatt tgtttgtatg tttttttctc atttcgtttg tgggtttttt2500 tttccaactg tgatctcgcc ttgtttctta caagcaaacc agggtccctt 2550cttggcacgt aacatgtacg tatttctgaa atattaaata gctgtacaga 2600 agcaggttttatttatcatg ttatcttatt aaaagaaaaa gcccaaaaag 2650 c 2651 24 556 PRT HomoSapien 24 Met Ala Arg Phe Gly Leu Pro Ala Leu Leu Cys Thr Leu Ala Val 15 10 15 Leu Ser Ala Ala Leu Leu Ala Ala Glu Leu Lys Ser Lys Ser Cys 2025 30 Ser Glu Val Arg Arg Leu Tyr Val Ser Lys Gly Phe Asn Lys Asn 35 4045 Asp Ala Pro Leu His Glu Ile Asn Gly Asp His Leu Lys Ile Cys 50 55 60Pro Gln Gly Ser Thr Cys Cys Ser Gln Glu Met Glu Glu Lys Tyr 65 70 75 SerLeu Gln Ser Lys Asp Asp Phe Lys Ser Val Val Ser Glu Gln 80 85 90 Cys AsnHis Leu Gln Ala Val Phe Ala Ser Arg Tyr Lys Lys Phe 95 100 105 Asp GluPhe Phe Lys Glu Leu Leu Glu Asn Ala Glu Lys Ser Leu 110 115 120 Asn AspMet Phe Val Lys Thr Tyr Gly His Leu Tyr Met Gln Asn 125 130 135 Ser GluLeu Phe Lys Asp Leu Phe Val Glu Leu Lys Arg Tyr Tyr 140 145 150 Val ValGly Asn Val Asn Leu Glu Glu Met Leu Asn Asp Phe Trp 155 160 165 Ala ArgLeu Leu Glu Arg Met Phe Arg Leu Val Asn Ser Gln Tyr 170 175 180 His PheThr Asp Glu Tyr Leu Glu Cys Val Ser Lys Tyr Thr Glu 185 190 195 Gln LeuLys Pro Phe Gly Asp Val Pro Arg Lys Leu Lys Leu Gln 200 205 210 Val ThrArg Ala Phe Val Ala Ala Arg Thr Phe Ala Gln Gly Leu 215 220 225 Ala ValAla Gly Asp Val Val Ser Lys Val Ser Val Val Asn Pro 230 235 240 Thr AlaGln Cys Thr His Ala Leu Leu Lys Met Ile Tyr Cys Ser 245 250 255 His CysArg Gly Leu Val Thr Val Lys Pro Cys Tyr Asn Tyr Cys 260 265 270 Ser AsnIle Met Arg Gly Cys Leu Ala Asn Gln Gly Asp Leu Asp 275 280 285 Phe GluTrp Asn Asn Phe Ile Asp Ala Met Leu Met Val Ala Glu 290 295 300 Arg LeuGlu Gly Pro Phe Asn Ile Glu Ser Val Met Asp Pro Ile 305 310 315 Asp ValLys Ile Ser Asp Ala Ile Met Asn Met Gln Asp Asn Ser 320 325 330 Val GlnVal Ser Gln Lys Val Phe Gln Gly Cys Gly Pro Pro Lys 335 340 345 Pro LeuPro Ala Gly Arg Ile Ser Arg Ser Ile Ser Glu Ser Ala 350 355 360 Phe SerAla Arg Phe Arg Pro His His Pro Glu Glu Arg Pro Thr 365 370 375 Thr AlaAla Gly Thr Ser Leu Asp Arg Leu Val Thr Asp Val Lys 380 385 390 Glu LysLeu Lys Gln Ala Lys Lys Phe Trp Ser Ser Leu Pro Ser 395 400 405 Asn ValCys Asn Asp Glu Arg Met Ala Ala Gly Asn Gly Asn Glu 410 415 420 Asp AspCys Trp Asn Gly Lys Gly Lys Ser Arg Tyr Leu Phe Ala 425 430 435 Val ThrGly Asn Gly Leu Ala Asn Gln Gly Asn Asn Pro Glu Val 440 445 450 Gln ValAsp Thr Ser Lys Pro Asp Ile Leu Ile Leu Arg Gln Ile 455 460 465 Met AlaLeu Arg Val Met Thr Ser Lys Met Lys Asn Ala Tyr Asn 470 475 480 Gly AsnAsp Val Asp Phe Phe Asp Ile Ser Asp Glu Ser Ser Gly 485 490 495 Glu GlySer Gly Ser Gly Cys Glu Tyr Gln Gln Cys Pro Ser Glu 500 505 510 Phe AspTyr Asn Ala Thr Asp His Ala Gly Lys Ser Ala Asn Glu 515 520 525 Lys AlaAsp Ser Ala Gly Val Arg Pro Gly Ala Gln Ala Tyr Leu 530 535 540 Leu ThrVal Phe Cys Ile Leu Phe Leu Val Met Gln Arg Glu Trp 545 550 555 Arg 25870 DNA Homo Sapien 25 ctcgccctca aatgggaacg ctggcctggg actaaagcatagaccaccag 50 gctgagtatc ctgacctgag tcatccccag ggatcaggag cctccagcag 100ggaaccttcc attatattct tcaagcaact tacagctgca ccgacagttg 150 cgatgaaagttctaatctct tccctcctcc tgttgctgcc actaatgctg 200 atgtccatgg tctctagcagcctgaatcca ggggtcgcca gaggccacag 250 ggaccgaggc caggcttcta ggagatggctccaggaaggc ggccaagaat 300 gtgagtgcaa agattggttc ctgagagccc cgagaagaaaattcatgaca 350 gtgtctgggc tgccaaagaa gcagtgcccc tgtgatcatt tcaagggcaa400 tgtgaagaaa acaagacacc aaaggcacca cagaaagcca aacaagcatt 450ccagagcctg ccagcaattt ctcaaacaat gtcagctaag aagctttgct 500 ctgcctttgtaggagctctg agcgcccact cttccaatta aacattctca 550 gccaagaaga cagtgagcacacctaccaga cactcttctt ctcccacctc 600 actctcccac tgtacccacc cctaaatcattccagtgctc tcaaaaagca 650 tgtttttcaa gatcattttg tttgttgctc tctctagtgtcttcttctct 700 cgtcagtctt agcctgtgcc ctccccttac ccaggcttag gcttaattac750 ctgaaagatt ccaggaaact gtagcttcct agctagtgtc atttaacctt 800aaatgcaatc aggaaagtag caaacagaag tcaataaata tttttaaatg 850 tcaaaaaaaaaaaaaaaaaa 870 26 119 PRT Homo Sapien 26 Met Lys Val Leu Ile Ser Ser LeuLeu Leu Leu Leu Pro Leu Met 1 5 10 15 Leu Met Ser Met Val Ser Ser SerLeu Asn Pro Gly Val Ala Arg 20 25 30 Gly His Arg Asp Arg Gly Gln Ala SerArg Arg Trp Leu Gln Glu 35 40 45 Gly Gly Gln Glu Cys Glu Cys Lys Asp TrpPhe Leu Arg Ala Pro 50 55 60 Arg Arg Lys Phe Met Thr Val Ser Gly Leu ProLys Lys Gln Cys 65 70 75 Pro Cys Asp His Phe Lys Gly Asn Val Lys Lys ThrArg His Gln 80 85 90 Arg His His Arg Lys Pro Asn Lys His Ser Arg Ala CysGln Gln 95 100 105 Phe Leu Lys Gln Cys Gln Leu Arg Ser Phe Ala Leu ProLeu 110 115 27 1371 DNA Homo Sapien 27 ggacgccagc gcctgcagag gctgagcagggaaaaagcca gtgccccagc 50 ggaagcacag ctcagagctg gtctgccatg gacatcctggtcccactcct 100 gcagctgctg gtgctgcttc ttaccctgcc cctgcacctc atggctctgc150 tgggctgctg gcagcccctg tgcaaaagct acttccccta cctgatggcc 200gtgctgactc ccaagagcaa ccgcaagatg gagagcaaga aacgggagct 250 cttcagccagataaaggggc ttacaggagc ctccgggaaa gtggccctac 300 tggagctggg ctgcggaaccggagccaact ttcagttcta cccaccgggc 350 tgcagggtca cctgcctaga cccaaatccccactttgaga agttcctgac 400 aaagagcatg gctgagaaca ggcacctcca atatgagcggtttgtggtgg 450 ctcctggaga ggacatgaga cagctggctg atggctccat ggatgtggtg500 gtctgcactc tggtgctgtg ctctgtgcag agcccaagga aggtcctgca 550ggaggtccgg agagtactga gaccgggagg tgtgctcttt ttctgggagc 600 atgtggcagaaccatatgga agctgggcct tcatgtggca gcaagttttc 650 gagcccacct ggaaacacattggggatggc tgctgcctca ccagagagac 700 ctggaaggat cttgagaacg cccagttctccgaaatccaa atggaacgac 750 agccccctcc cttgaagtgg ctacctgttg ggccccacatcatgggaaag 800 gctgtcaaac aatctttccc aagctccaag gcactcattt gctccttccc850 cagcctccaa ttagaacaag ccacccacca gcctatctat cttccactga 900gagggaccta gcagaatgag agaagacatt catgtaccac ctactagtcc 950 ctctctccccaacctctgcc agggcaatct ctaacttcaa tcccgccttc 1000 gacagtgaaa aagctctacttctacgctga cccagggagg aaacactagg 1050 accctgttgt atcctcaact gcaagtttctggactagtct cccaacgttt 1100 gcctcccaat gttgtccctt tccttcgttc ccatggtaaagctcctctcg 1150 ctttcctcct gaggctacac ccatgcgtct ctaggaactg gtcacaaaag1200 tcatggtgcc tgcatccctg ccaagccccc ctgaccctct ctccccacta 1250ccaccttctt cctgagctgg gggcaccagg gagaatcaga gatgctgggg 1300 atgccagagcaagactcaaa gaggcagagg ttttgttctc aaatattttt 1350 taataaatag acgaaaccac g1371 28 277 PRT Homo Sapien 28 Met Asp Ile Leu Val Pro Leu Leu Gln LeuLeu Val Leu Leu Leu 1 5 10 15 Thr Leu Pro Leu His Leu Met Ala Leu LeuGly Cys Trp Gln Pro 20 25 30 Leu Cys Lys Ser Tyr Phe Pro Tyr Leu Met AlaVal Leu Thr Pro 35 40 45 Lys Ser Asn Arg Lys Met Glu Ser Lys Lys Arg GluLeu Phe Ser 50 55 60 Gln Ile Lys Gly Leu Thr Gly Ala Ser Gly Lys Val AlaLeu Leu 65 70 75 Glu Leu Gly Cys Gly Thr Gly Ala Asn Phe Gln Phe Tyr ProPro 80 85 90 Gly Cys Arg Val Thr Cys Leu Asp Pro Asn Pro His Phe Glu Lys95 100 105 Phe Leu Thr Lys Ser Met Ala Glu Asn Arg His Leu Gln Tyr Glu110 115 120 Arg Phe Val Val Ala Pro Gly Glu Asp Met Arg Gln Leu Ala Asp125 130 135 Gly Ser Met Asp Val Val Val Cys Thr Leu Val Leu Cys Ser Val140 145 150 Gln Ser Pro Arg Lys Val Leu Gln Glu Val Arg Arg Val Leu Arg155 160 165 Pro Gly Gly Val Leu Phe Phe Trp Glu His Val Ala Glu Pro Tyr170 175 180 Gly Ser Trp Ala Phe Met Trp Gln Gln Val Phe Glu Pro Thr Trp185 190 195 Lys His Ile Gly Asp Gly Cys Cys Leu Thr Arg Glu Thr Trp Lys200 205 210 Asp Leu Glu Asn Ala Gln Phe Ser Glu Ile Gln Met Glu Arg Gln215 220 225 Pro Pro Pro Leu Lys Trp Leu Pro Val Gly Pro His Ile Met Gly230 235 240 Lys Ala Val Lys Gln Ser Phe Pro Ser Ser Lys Ala Leu Ile Cys245 250 255 Ser Phe Pro Ser Leu Gln Leu Glu Gln Ala Thr His Gln Pro Ile260 265 270 Tyr Leu Pro Leu Arg Gly Thr 275 29 494 DNA Homo Sapien 29caatgtttgc ctatccacct cccccaagcc cctttaccta tgctgctgct 50 aacgctgctgctgctgctgc tgctgcttaa aggctcatgc ttggagtggg 100 gactggtcgg tgcccagaaagtctcttctg ccactgacgc ccccatcagg 150 gattgggcct tctttccccc ttcctttctgtgtctcctgc ctcatcggcc 200 tgccatgacc tgcagccaag cccagccccg tggggaaggggagaaagtgg 250 gggatggcta agaaagctgg gagataggga acagaagagg gtagtgggtg300 ggctaggggg gctgccttat ttaaagtggt tgtttatgat tcttatacta 350atttatacaa agatattaag gccctgttca ttaagaaatt gttcccttcc 400 cctgtgttcaatgtttgtaa agattgttct gtgtaaatat gtctttataa 450 taaacagtta aaagctgaaaaaaaaaaaaa aaaaaaaaaa aaaa 494 30 73 PRT Homo Sapien 30 Met Leu Leu LeuThr Leu Leu Leu Leu Leu Leu Leu Leu Lys Gly 1 5 10 15 Ser Cys Leu GluTrp Gly Leu Val Gly Ala Gln Lys Val Ser Ser 20 25 30 Ala Thr Asp Ala ProIle Arg Asp Trp Ala Phe Phe Pro Pro Ser 35 40 45 Phe Leu Cys Leu Leu ProHis Arg Pro Ala Met Thr Cys Ser Gln 50 55 60 Ala Gln Pro Arg Gly Glu GlyGlu Lys Val Gly Asp Gly 65 70 31 1660 DNA Homo Sapien 31 gtttgaattccttcaactat acccacagtc caaaagcaga ctcactgtgt 50 cccaggctac cagttcctccaagcaagtca tttcccttat ttaaccgatg 100 tgtccctcaa acacctgagt gctactccctatttgcatct gttttgataa 150 atgatgttga caccctccac cgaattctaa gtggaatcatgtcgggaaga 200 gatacaatcc ttggcctgtg tatcctcgca ttagccttgt ctttggccat250 gatgtttacc ttcagattca tcaccaccct tctggttcac attttcattt 300cattggttat tttgggattg ttgtttgtct gcggtgtttt atggtggctg 350 tattatgactataccaacga cctcagcata gaattggaca cagaaaggga 400 aaatatgaag tgcgtgctggggtttgctat cgtatccaca ggcatcacgg 450 cagtgctgct cgtcttgatt tttgttctcagaaagagaat aaaattgaca 500 gttgagcttt tccaaatcac aaataaagcc atcagcagtgctcccttcct 550 gctgttccag ccactgtgga catttgccat cctcattttc ttctgggtcc600 tctgggtggc tgtgctgctg agcctgggaa ctgcaggagc tgcccaggtt 650atggaaggcg gccaagtgga atataagccc ctttcgggca ttcggtacat 700 gtggtcgtaccatttaattg gcctcatctg gactagtgaa ttcatccttg 750 cgtgccagca aatgactatagctggggcag tggttacttg ttatttcaac 800 agaagtaaaa atgatcctcc tgatcatcccatcctttcgt ctctctccat 850 tctcttcttc taccatcaag gaaccgttgt gaaagggtcatttttaatct 900 ctgtggtgag gattccgaga atcattgtca tgtacatgca aaacgcactg950 aaagaacagc agcatggtgc attgtccagg tacctgttcc gatgctgcta 1000ctgctgtttc tggtgtcttg acaaatacct gctccatctc aaccagaatg 1050 catatactacaactgctatt aatgggacag atttctgtac atcagcaaaa 1100 gatgcattca aaatcttgtccaagaactca agtcacttta catctattaa 1150 ctgctttgga gacttcataa tttttctaggaaaggtgtta gtggtgtgtt 1200 tcactgtttt tggaggactc atggctttta actacaatcgggcattccag 1250 gtgtgggcag tccctctgtt attggtagct ttttttgcct acttagtagc1300 ccatagtttt ttatctgtgt ttgaaactgt gctggatgca cttttcctgt 1350gttttgctgt tgatctggaa acaaatgatg gatcgtcaga aaagccctac 1400 tttatggatcaagaatttct gagtttcgta aaaaggagca acaaattaaa 1450 caatgcaagg gcacagcaggacaagcactc attaaggaat gaggagggaa 1500 cagaactcca ggccattgtg agatagatacccatttaggt atctgtacct 1550 ggaaaacatt tccttctaag agccatttac agaatagaagatgagaccac 1600 tagagaaaag ttagtgaatt tttttttaaa agacctaata aaccctattc1650 ttcctcaaaa 1660 32 445 PRT Homo Sapien 32 Met Ser Gly Arg Asp ThrIle Leu Gly Leu Cys Ile Leu Ala Leu 1 5 10 15 Ala Leu Ser Leu Ala MetMet Phe Thr Phe Arg Phe Ile Thr Thr 20 25 30 Leu Leu Val His Ile Phe IleSer Leu Val Ile Leu Gly Leu Leu 35 40 45 Phe Val Cys Gly Val Leu Trp TrpLeu Tyr Tyr Asp Tyr Thr Asn 50 55 60 Asp Leu Ser Ile Glu Leu Asp Thr GluArg Glu Asn Met Lys Cys 65 70 75 Val Leu Gly Phe Ala Ile Val Ser Thr GlyIle Thr Ala Val Leu 80 85 90 Leu Val Leu Ile Phe Val Leu Arg Lys Arg IleLys Leu Thr Val 95 100 105 Glu Leu Phe Gln Ile Thr Asn Lys Ala Ile SerSer Ala Pro Phe 110 115 120 Leu Leu Phe Gln Pro Leu Trp Thr Phe Ala IleLeu Ile Phe Phe 125 130 135 Trp Val Leu Trp Val Ala Val Leu Leu Ser LeuGly Thr Ala Gly 140 145 150 Ala Ala Gln Val Met Glu Gly Gly Gln Val GluTyr Lys Pro Leu 155 160 165 Ser Gly Ile Arg Tyr Met Trp Ser Tyr His LeuIle Gly Leu Ile 170 175 180 Trp Thr Ser Glu Phe Ile Leu Ala Cys Gln GlnMet Thr Ile Ala 185 190 195 Gly Ala Val Val Thr Cys Tyr Phe Asn Arg SerLys Asn Asp Pro 200 205 210 Pro Asp His Pro Ile Leu Ser Ser Leu Ser IleLeu Phe Phe Tyr 215 220 225 His Gln Gly Thr Val Val Lys Gly Ser Phe LeuIle Ser Val Val 230 235 240 Arg Ile Pro Arg Ile Ile Val Met Tyr Met GlnAsn Ala Leu Lys 245 250 255 Glu Gln Gln His Gly Ala Leu Ser Arg Tyr LeuPhe Arg Cys Cys 260 265 270 Tyr Cys Cys Phe Trp Cys Leu Asp Lys Tyr LeuLeu His Leu Asn 275 280 285 Gln Asn Ala Tyr Thr Thr Thr Ala Ile Asn GlyThr Asp Phe Cys 290 295 300 Thr Ser Ala Lys Asp Ala Phe Lys Ile Leu SerLys Asn Ser Ser 305 310 315 His Phe Thr Ser Ile Asn Cys Phe Gly Asp PheIle Ile Phe Leu 320 325 330 Gly Lys Val Leu Val Val Cys Phe Thr Val PheGly Gly Leu Met 335 340 345 Ala Phe Asn Tyr Asn Arg Ala Phe Gln Val TrpAla Val Pro Leu 350 355 360 Leu Leu Val Ala Phe Phe Ala Tyr Leu Val AlaHis Ser Phe Leu 365 370 375 Ser Val Phe Glu Thr Val Leu Asp Ala Leu PheLeu Cys Phe Ala 380 385 390 Val Asp Leu Glu Thr Asn Asp Gly Ser Ser GluLys Pro Tyr Phe 395 400 405 Met Asp Gln Glu Phe Leu Ser Phe Val Lys ArgSer Asn Lys Leu 410 415 420 Asn Asn Ala Arg Ala Gln Gln Asp Lys His SerLeu Arg Asn Glu 425 430 435 Glu Gly Thr Glu Leu Gln Ala Ile Val Arg 440445 33 2773 DNA Homo Sapien 33 gttcgattag ctcctctgag aagaagagaaaaggttcttg gacctctccc 50 tgtttcttcc ttagaataat ttgtatggga tttgtgatgcaggaaagcct 100 aagggaaaaa gaatattcat tctgtgtggt gaaaattttt tgaaaaaaaa150 attgccttct tcaaacaagg gtgtcattct gatatttatg aggactgttg 200ttctcactat gaaggcatct gttattgaaa tgttccttgt tttgctggtg 250 actggagtacattcaaacaa agaaacggca aagaagatta aaaggcccaa 300 gttcactgtg cctcagatcaactgcgatgt caaagccgga aagatcatcg 350 atcctgagtt cattgtgaaa tgtccagcaggatgccaaga ccccaaatac 400 catgtttatg gcactgacgt gtatgcatcc tactccagtgtgtgtggcgc 450 tgccgtacac agtggtgtgc ttgataattc aggagggaaa atacttgttc500 ggaaggttgc tggacagtct ggttacaaag ggagttattc caacggtgtc 550caatcgttat ccctaccacg atggagagaa tcctttatcg tcttagaaag 600 taaacccaaaaagggtgtaa cctacccatc agctcttaca tactcatcat 650 cgaaaagtcc agctgcccaagcaggtgaga ccacaaaagc ctatcagagg 700 ccacctattc cagggacaac tgcacagccggtcactctga tgcagcttct 750 ggctgtcact gtagctgtgg ccacccccac caccttgccaaggccatccc 800 cttctgctgc ttctaccacc agcatcccca gaccacaatc agtgggccac850 aggagccagg agatggatct ctggtccact gccacctaca caagcagcca 900aaacaggccc agagctgatc caggtatcca aaggcaagat ccttcaggag 950 ctgccttccagaaacctgtt ggagcggatg tcagcctggg acttgttcca 1000 aaagaagaat tgagcacacagtctttggag ccagtatccc tgggagatcc 1050 aaactgcaaa attgacttgt cgtttttaattgatgggagc accagcattg 1100 gcaaacggcg attccgaatc cagaagcagc tcctggctgatgttgcccaa 1150 gctcttgaca ttggccctgc cggtccactg atgggtgttg tccagtatgg1200 agacaaccct gctactcact ttaacctcaa gacacacacg aattctcgag 1250atctgaagac agccatagag aaaattactc agagaggagg actttctaat 1300 gtaggtcgggccatctcctt tgtgaccaag aacttctttt ccaaagccaa 1350 tggaaacaga agcggggctcccaatgtggt ggtggtgatg gtggatggct 1400 ggcccacgga caaagtggag gaggcttcaagacttgcgag agagtcagga 1450 atcaacattt tcttcatcac cattgaaggt gctgctgaaaatgagaagca 1500 gtatgtggtg gagcccaact ttgcaaacaa ggccgtgtgc agaacaaacg1550 gcttctactc gctccacgtg cagagctggt ttggcctcca caagaccctg 1600cagcctctgg tgaagcgggt ctgcgacact gaccgcctgg cctgcagcaa 1650 gacctgcttgaactcggctg acattggctt cgtcatcgac ggctccagca 1700 gtgtggggac gggcaacttccgcaccgtcc tccagtttgt gaccaacctc 1750 accaaagagt ttgagatttc cgacacggacacgcgcatcg gggccgtgca 1800 gtacacctac gaacagcggc tggagtttgg gttcgacaagtacagcagca 1850 agcctgacat cctcaacgcc atcaagaggg tgggctactg gagtggtggc1900 accagcacgg gggctgccat caacttcgcc ctggagcagc tcttcaagaa 1950gtccaagccc aacaagagga agttaatgat cctcatcacc gacgggaggt 2000 cctacgacgacgtccggatc ccagccatgg ctgcccatct gaagggagtg 2050 atcacctatg cgataggcgttgcctgggct gcccaagagg agctagaagt 2100 cattgccact caccccgcca gagaccactccttctttgtg gacgagtttg 2150 acaacctcca tcagtatgtc cccaggatca tccagaacatttgtacagag 2200 ttcaactcac agcctcggaa ctgaattcag agcaggcaga gcaccagcaa2250 gtgctgcttt actaactgac gtgttggacc accccaccgc ttaatggggc 2300acgcacggtg catcaagtct tgggcagggc atggagaaac aaatgtcttg 2350 ttattattctttgccatcat gctttttcat attccaaaac ttggagttac 2400 aaagatgatc acaaacgtatagaatgagcc aaaaggctac atcatgttga 2450 gggtgctgga gattttacat tttgacaattgttttcaaaa taaatgttcg 2500 gaatacagtg cagcccttac gacaggctta cgtagagcttttgtgagatt 2550 tttaagttgt tatttctgat ttgaactctg taaccctcag caagtttcat2600 ttttgtcatg acaatgtagg aattgctgaa ttaaatgttt agaaggatga 2650aaaataaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 2700 aaaaaaaaaaaaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 2750 aaaaaaaaaa aaaaaaaaaaaag 2773 34 678 PRT Homo Sapien 34 Met Arg Thr Val Val Leu Thr Met LysAla Ser Val Ile Glu Met 1 5 10 15 Phe Leu Val Leu Leu Val Thr Gly ValHis Ser Asn Lys Glu Thr 20 25 30 Ala Lys Lys Ile Lys Arg Pro Lys Phe ThrVal Pro Gln Ile Asn 35 40 45 Cys Asp Val Lys Ala Gly Lys Ile Ile Asp ProGlu Phe Ile Val 50 55 60 Lys Cys Pro Ala Gly Cys Gln Asp Pro Lys Tyr HisVal Tyr Gly 65 70 75 Thr Asp Val Tyr Ala Ser Tyr Ser Ser Val Cys Gly AlaAla Val 80 85 90 His Ser Gly Val Leu Asp Asn Ser Gly Gly Lys Ile Leu ValArg 95 100 105 Lys Val Ala Gly Gln Ser Gly Tyr Lys Gly Ser Tyr Ser AsnGly 110 115 120 Val Gln Ser Leu Ser Leu Pro Arg Trp Arg Glu Ser Phe IleVal 125 130 135 Leu Glu Ser Lys Pro Lys Lys Gly Val Thr Tyr Pro Ser AlaLeu 140 145 150 Thr Tyr Ser Ser Ser Lys Ser Pro Ala Ala Gln Ala Gly GluThr 155 160 165 Thr Lys Ala Tyr Gln Arg Pro Pro Ile Pro Gly Thr Thr AlaGln 170 175 180 Pro Val Thr Leu Met Gln Leu Leu Ala Val Thr Val Ala ValAla 185 190 195 Thr Pro Thr Thr Leu Pro Arg Pro Ser Pro Ser Ala Ala SerThr 200 205 210 Thr Ser Ile Pro Arg Pro Gln Ser Val Gly His Arg Ser GlnGlu 215 220 225 Met Asp Leu Trp Ser Thr Ala Thr Tyr Thr Ser Ser Gln AsnArg 230 235 240 Pro Arg Ala Asp Pro Gly Ile Gln Arg Gln Asp Pro Ser GlyAla 245 250 255 Ala Phe Gln Lys Pro Val Gly Ala Asp Val Ser Leu Gly LeuVal 260 265 270 Pro Lys Glu Glu Leu Ser Thr Gln Ser Leu Glu Pro Val SerLeu 275 280 285 Gly Asp Pro Asn Cys Lys Ile Asp Leu Ser Phe Leu Ile AspGly 290 295 300 Ser Thr Ser Ile Gly Lys Arg Arg Phe Arg Ile Gln Lys GlnLeu 305 310 315 Leu Ala Asp Val Ala Gln Ala Leu Asp Ile Gly Pro Ala GlyPro 320 325 330 Leu Met Gly Val Val Gln Tyr Gly Asp Asn Pro Ala Thr HisPhe 335 340 345 Asn Leu Lys Thr His Thr Asn Ser Arg Asp Leu Lys Thr AlaIle 350 355 360 Glu Lys Ile Thr Gln Arg Gly Gly Leu Ser Asn Val Gly ArgAla 365 370 375 Ile Ser Phe Val Thr Lys Asn Phe Phe Ser Lys Ala Asn GlyAsn 380 385 390 Arg Ser Gly Ala Pro Asn Val Val Val Val Met Val Asp GlyTrp 395 400 405 Pro Thr Asp Lys Val Glu Glu Ala Ser Arg Leu Ala Arg GluSer 410 415 420 Gly Ile Asn Ile Phe Phe Ile Thr Ile Glu Gly Ala Ala GluAsn 425 430 435 Glu Lys Gln Tyr Val Val Glu Pro Asn Phe Ala Asn Lys AlaVal 440 445 450 Cys Arg Thr Asn Gly Phe Tyr Ser Leu His Val Gln Ser TrpPhe 455 460 465 Gly Leu His Lys Thr Leu Gln Pro Leu Val Lys Arg Val CysAsp 470 475 480 Thr Asp Arg Leu Ala Cys Ser Lys Thr Cys Leu Asn Ser AlaAsp 485 490 495 Ile Gly Phe Val Ile Asp Gly Ser Ser Ser Val Gly Thr GlyAsn 500 505 510 Phe Arg Thr Val Leu Gln Phe Val Thr Asn Leu Thr Lys GluPhe 515 520 525 Glu Ile Ser Asp Thr Asp Thr Arg Ile Gly Ala Val Gln TyrThr 530 535 540 Tyr Glu Gln Arg Leu Glu Phe Gly Phe Asp Lys Tyr Ser SerLys 545 550 555 Pro Asp Ile Leu Asn Ala Ile Lys Arg Val Gly Tyr Trp SerGly 560 565 570 Gly Thr Ser Thr Gly Ala Ala Ile Asn Phe Ala Leu Glu GlnLeu 575 580 585 Phe Lys Lys Ser Lys Pro Asn Lys Arg Lys Leu Met Ile LeuIle 590 595 600 Thr Asp Gly Arg Ser Tyr Asp Asp Val Arg Ile Pro Ala MetAla 605 610 615 Ala His Leu Lys Gly Val Ile Thr Tyr Ala Ile Gly Val AlaTrp 620 625 630 Ala Ala Gln Glu Glu Leu Glu Val Ile Ala Thr His Pro AlaArg 635 640 645 Asp His Ser Phe Phe Val Asp Glu Phe Asp Asn Leu His GlnTyr 650 655 660 Val Pro Arg Ile Ile Gln Asn Ile Cys Thr Glu Phe Asn SerGln 665 670 675 Pro Arg Asn 35 2095 DNA Homo Sapien 35 ccgagcacaggagattgcct gcgtttagga ggtggctgcg ttgtgggaaa 50 agctatcaag gaagaaattgccaaaccatg tctttttttc tgttttcaga 100 gtagttcaca acagatctga gtgttttaattaagcatgga atacagaaaa 150 caacaaaaaa cttaagcttt aatttcatct ggaattccacagttttctta 200 gctccctgga cccggttgac ctgttggctc ttcccgctgg ctgctctatc250 acgtggtgct ctccgactac tcaccccgag tgtaaagaac cttcggctcg 300cgtgcttctg agctgctgtg gatggcctcg gctctctgga ctgtccttcc 350 gagtaggatgtcactgagat ccctcaaatg gagcctcctg ctgctgtcac 400 tcctgagttt ctttgtgatgtggtacctca gccttcccca ctacaatgtg 450 atagaacgcg tgaactggat gtacttctatgagtatgagc cgatttacag 500 acaagacttt cacttcacac ttcgagagca ttcaaactgctctcatcaaa 550 atccatttct ggtcattctg gtgacctccc acccttcaga tgtgaaagcc600 aggcaggcca ttagagttac ttggggtgaa aaaaagtctt ggtggggata 650tgaggttctt acatttttct tattaggcca agaggctgaa aaggaagaca 700 aaatgttggcattgtcctta gaggatgaac accttcttta tggtgacata 750 atccgacaag attttttagacacatataat aacctgacct tgaaaaccat 800 tatggcattc aggtgggtaa ctgagttttgccccaatgcc aagtacgtaa 850 tgaagacaga cactgatgtt ttcatcaata ctggcaatttagtgaagtat 900 cttttaaacc taaaccactc agagaagttt ttcacaggtt atcctctaat950 tgataattat tcctatagag gattttacca aaaaacccat atttcttacc 1000aggagtatcc tttcaaggtg ttccctccat actgcagtgg gttgggttat 1050 ataatgtccagagatttggt gccaaggatc tatgaaatga tgggtcacgt 1100 aaaacccatc aagtttgaagatgtttatgt cgggatctgt ttgaatttat 1150 taaaagtgaa cattcatatt ccagaagacacaaatctttt ctttctatat 1200 agaatccatt tggatgtctg tcaactgaga cgtgtgattgcagcccatgg 1250 cttttcttcc aaggagatca tcactttttg gcaggtcatg ctaaggaaca1300 ccacatgcca ttattaactt cacattctac aaaaagccta gaaggacagg 1350ataccttgtg gaaagtgtta aataaagtag gtactgtgga aaattcatgg 1400 ggaggtcagtgtgctggctt acactgaact gaaactcatg aaaaacccag 1450 actggagact ggagggttacacttgtgatt tattagtcag gcccttcaaa 1500 gatgatatgt ggaggaatta aatataaaggaattggaggt ttttgctaaa 1550 gaaattaata ggaccaaaca atttggacat gtcattctgtagactagaat 1600 ttcttaaaag ggtgttactg agttataagc tcactaggct gtaaaaacaa1650 aacaatgtag agttttattt attgaacaat gtagtcactt gaaggttttg 1700tgtatatctt atgtggatta ccaatttaaa aatatatgta gttctgtgtc 1750 aaaaaacttcttcactgaag ttatactgaa caaaatttta cctgtttttg 1800 gtcatttata aagtacttcaagatgttgca gtatttcaca gttattatta 1850 tttaaaatta cttcaacttt gtgtttttaaatgttttgac gatttcaata 1900 caagataaaa aggatagtga atcattcttt acatgcaaacattttccagt 1950 tacttaactg atcagtttat tattgataca tcactccatt aatgtaaagt2000 cataggtcat tattgcatat cagtaatctc ttggactttg ttaaatattt 2050tactgtggta atatagagaa gaattaaagc aagaaaatct gaaaa 2095 36 331 PRT HomoSapien 36 Met Ala Ser Ala Leu Trp Thr Val Leu Pro Ser Arg Met Ser Leu 15 10 15 Arg Ser Leu Lys Trp Ser Leu Leu Leu Leu Ser Leu Leu Ser Phe 2025 30 Phe Val Met Trp Tyr Leu Ser Leu Pro His Tyr Asn Val Ile Glu 35 4045 Arg Val Asn Trp Met Tyr Phe Tyr Glu Tyr Glu Pro Ile Tyr Arg 50 55 60Gln Asp Phe His Phe Thr Leu Arg Glu His Ser Asn Cys Ser His 65 70 75 GlnAsn Pro Phe Leu Val Ile Leu Val Thr Ser His Pro Ser Asp 80 85 90 Val LysAla Arg Gln Ala Ile Arg Val Thr Trp Gly Glu Lys Lys 95 100 105 Ser TrpTrp Gly Tyr Glu Val Leu Thr Phe Phe Leu Leu Gly Gln 110 115 120 Glu AlaGlu Lys Glu Asp Lys Met Leu Ala Leu Ser Leu Glu Asp 125 130 135 Glu HisLeu Leu Tyr Gly Asp Ile Ile Arg Gln Asp Phe Leu Asp 140 145 150 Thr TyrAsn Asn Leu Thr Leu Lys Thr Ile Met Ala Phe Arg Trp 155 160 165 Val ThrGlu Phe Cys Pro Asn Ala Lys Tyr Val Met Lys Thr Asp 170 175 180 Thr AspVal Phe Ile Asn Thr Gly Asn Leu Val Lys Tyr Leu Leu 185 190 195 Asn LeuAsn His Ser Glu Lys Phe Phe Thr Gly Tyr Pro Leu Ile 200 205 210 Asp AsnTyr Ser Tyr Arg Gly Phe Tyr Gln Lys Thr His Ile Ser 215 220 225 Tyr GlnGlu Tyr Pro Phe Lys Val Phe Pro Pro Tyr Cys Ser Gly 230 235 240 Leu GlyTyr Ile Met Ser Arg Asp Leu Val Pro Arg Ile Tyr Glu 245 250 255 Met MetGly His Val Lys Pro Ile Lys Phe Glu Asp Val Tyr Val 260 265 270 Gly IleCys Leu Asn Leu Leu Lys Val Asn Ile His Ile Pro Glu 275 280 285 Asp ThrAsn Leu Phe Phe Leu Tyr Arg Ile His Leu Asp Val Cys 290 295 300 Gln LeuArg Arg Val Ile Ala Ala His Gly Phe Ser Ser Lys Glu 305 310 315 Ile IleThr Phe Trp Gln Val Met Leu Arg Asn Thr Thr Cys His 320 325 330 Tyr 372846 DNA Homo Sapien 37 cgctcgggca ccagccgcgg caaggatgga gctgggttgctggacgcagt 50 tggggctcac ttttcttcag ctccttctca tctcgtcctt gccaagagag 100tacacagtca ttaatgaagc ctgccctgga gcagagtgga atatcatgtg 150 tcgggagtgctgtgaatatg atcagattga gtgcgtctgc cccggaaaga 200 gggaagtcgt gggttataccatcccttgct gcaggaatga ggagaatgag 250 tgtgactcct gcctgatcca cccaggttgtaccatctttg aaaactgcaa 300 gagctgccga aatggctcat gggggggtac cttggatgacttctatgtga 350 aggggttcta ctgtgcagag tgccgagcag gctggtacgg aggagactgc400 atgcgatgtg gccaggttct gcgagcccca aagggtcaga ttttgttgga 450aagctatccc ctaaatgctc actgtgaatg gaccattcat gctaaacctg 500 ggtttgtcatccaactaaga tttgtcatgt tgagtctgga gtttgactac 550 atgtgccagt atgactatgttgaggttcgt gatggagaca accgcgatgg 600 ccagatcatc aagcgtgtct gtggcaacgagcggccagct cctatccaga 650 gcataggatc ctcactccac gtcctcttcc actccgatggctccaagaat 700 tttgacggtt tccatgccat ttatgaggag atcacagcat gctcctcatc750 cccttgtttc catgacggca cgtgcgtcct tgacaaggct ggatcttaca 800agtgtgcctg cttggcaggc tatactgggc agcgctgtga aaatctcctt 850 gaagaaagaaactgctcaga ccctgggggc ccagtcaatg ggtaccagaa 900 aataacaggg ggccctgggcttatcaacgg acgccatgct aaaattggca 950 ccgtggtgtc tttcttttgt aacaactcctatgttcttag tggcaatgag 1000 aaaagaactt gccagcagaa tggagagtgg tcagggaaacagcccatctg 1050 cataaaagcc tgccgagaac caaagatttc agacctggtg agaaggagag1100 ttcttccgat gcaggttcag tcaagggaga caccattaca ccagctatac 1150tcagcggcct tcagcaagca gaaactgcag agtgccccta ccaagaagcc 1200 agcccttccctttggagatc tgcccatggg ataccaacat ctgcataccc 1250 agctccagta tgagtgcatctcacccttct accgccgcct gggcagcagc 1300 aggaggacat gtctgaggac tgggaagtggagtgggcggg caccatcctg 1350 catccctatc tgcgggaaaa ttgagaacat cactgctccaaagacccaag 1400 ggttgcgctg gccgtggcag gcagccatct acaggaggac cagcggggtg1450 catgacggca gcctacacaa gggagcgtgg ttcctagtct gcagcggtgc 1500cctggtgaat gagcgcactg tggtggtggc tgcccactgt gttactgacc 1550 tggggaaggtcaccatgatc aagacagcag acctgaaagt tgttttgggg 1600 aaattctacc gggatgatgaccgggatgag aagaccatcc agagcctaca 1650 gatttctgct atcattctgc atcccaactatgaccccatc ctgcttgatg 1700 ctgacatcgc catcctgaag ctcctagaca aggcccgtatcagcacccga 1750 gtccagccca tctgcctcgc tgccagtcgg gatctcagca cttccttcca1800 ggagtcccac atcactgtgg ctggctggaa tgtcctggca gacgtgagga 1850gccctggctt caagaacgac acactgcgct ctggggtggt cagtgtggtg 1900 gactcgctgctgtgtgagga gcagcatgag gaccatggca tcccagtgag 1950 tgtcactgat aacatgttctgtgccagctg ggaacccact gccccttctg 2000 atatctgcac tgcagagaca ggaggcatcgcggctgtgtc cttcccggga 2050 cgagcatctc ctgagccacg ctggcatctg atgggactggtcagctggag 2100 ctatgataaa acatgcagcc acaggctctc cactgccttc accaaggtgc2150 tgccttttaa agactggatt gaaagaaata tgaaatgaac catgctcatg 2200cactccttga gaagtgtttc tgtatatccg tctgtacgtg tgtcattgcg 2250 tgaagcagtgtgggcctgaa gtgtgatttg gcctgtgaac ttggctgtgc 2300 cagggcttct gacttcagggacaaaactca gtgaagggtg agtagacctc 2350 cattgctggt aggctgatgc cgcgtccactactaggacag ccaattggaa 2400 gatgccaggg cttgcaagaa gtaagtttct tcaaagaagaccatatacaa 2450 aacctctcca ctccactgac ctggtggtct tccccaactt tcagttatac2500 gaatgccatc agcttgacca gggaagatct gggcttcatg aggccccttt 2550tgaggctctc aagttctaga gagctgcctg tgggacagcc cagggcagca 2600 gagctgggatgtggtgcatg cctttgtgta catggccaca gtacagtctg 2650 gtccttttcc ttccccatctcttgtacaca ttttaataaa ataagggttg 2700 gcttctgaac tacaaaaaaa aaaaaaaaaaaaaaaaaaaa aaaaaaaaaa 2750 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaaaaaaaaaaaa 2800 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaa 284638 720 PRT Homo Sapien 38 Met Glu Leu Gly Cys Trp Thr Gln Leu Gly LeuThr Phe Leu Gln 1 5 10 15 Leu Leu Leu Ile Ser Ser Leu Pro Arg Glu TyrThr Val Ile Asn 20 25 30 Glu Ala Cys Pro Gly Ala Glu Trp Asn Ile Met CysArg Glu Cys 35 40 45 Cys Glu Tyr Asp Gln Ile Glu Cys Val Cys Pro Gly LysArg Glu 50 55 60 Val Val Gly Tyr Thr Ile Pro Cys Cys Arg Asn Glu Glu AsnGlu 65 70 75 Cys Asp Ser Cys Leu Ile His Pro Gly Cys Thr Ile Phe Glu Asn80 85 90 Cys Lys Ser Cys Arg Asn Gly Ser Trp Gly Gly Thr Leu Asp Asp 95100 105 Phe Tyr Val Lys Gly Phe Tyr Cys Ala Glu Cys Arg Ala Gly Trp 110115 120 Tyr Gly Gly Asp Cys Met Arg Cys Gly Gln Val Leu Arg Ala Pro 125130 135 Lys Gly Gln Ile Leu Leu Glu Ser Tyr Pro Leu Asn Ala His Cys 140145 150 Glu Trp Thr Ile His Ala Lys Pro Gly Phe Val Ile Gln Leu Arg 155160 165 Phe Val Met Leu Ser Leu Glu Phe Asp Tyr Met Cys Gln Tyr Asp 170175 180 Tyr Val Glu Val Arg Asp Gly Asp Asn Arg Asp Gly Gln Ile Ile 185190 195 Lys Arg Val Cys Gly Asn Glu Arg Pro Ala Pro Ile Gln Ser Ile 200205 210 Gly Ser Ser Leu His Val Leu Phe His Ser Asp Gly Ser Lys Asn 215220 225 Phe Asp Gly Phe His Ala Ile Tyr Glu Glu Ile Thr Ala Cys Ser 230235 240 Ser Ser Pro Cys Phe His Asp Gly Thr Cys Val Leu Asp Lys Ala 245250 255 Gly Ser Tyr Lys Cys Ala Cys Leu Ala Gly Tyr Thr Gly Gln Arg 260265 270 Cys Glu Asn Leu Leu Glu Glu Arg Asn Cys Ser Asp Pro Gly Gly 275280 285 Pro Val Asn Gly Tyr Gln Lys Ile Thr Gly Gly Pro Gly Leu Ile 290295 300 Asn Gly Arg His Ala Lys Ile Gly Thr Val Val Ser Phe Phe Cys 305310 315 Asn Asn Ser Tyr Val Leu Ser Gly Asn Glu Lys Arg Thr Cys Gln 320325 330 Gln Asn Gly Glu Trp Ser Gly Lys Gln Pro Ile Cys Ile Lys Ala 335340 345 Cys Arg Glu Pro Lys Ile Ser Asp Leu Val Arg Arg Arg Val Leu 350355 360 Pro Met Gln Val Gln Ser Arg Glu Thr Pro Leu His Gln Leu Tyr 365370 375 Ser Ala Ala Phe Ser Lys Gln Lys Leu Gln Ser Ala Pro Thr Lys 380385 390 Lys Pro Ala Leu Pro Phe Gly Asp Leu Pro Met Gly Tyr Gln His 395400 405 Leu His Thr Gln Leu Gln Tyr Glu Cys Ile Ser Pro Phe Tyr Arg 410415 420 Arg Leu Gly Ser Ser Arg Arg Thr Cys Leu Arg Thr Gly Lys Trp 425430 435 Ser Gly Arg Ala Pro Ser Cys Ile Pro Ile Cys Gly Lys Ile Glu 440445 450 Asn Ile Thr Ala Pro Lys Thr Gln Gly Leu Arg Trp Pro Trp Gln 455460 465 Ala Ala Ile Tyr Arg Arg Thr Ser Gly Val His Asp Gly Ser Leu 470475 480 His Lys Gly Ala Trp Phe Leu Val Cys Ser Gly Ala Leu Val Asn 485490 495 Glu Arg Thr Val Val Val Ala Ala His Cys Val Thr Asp Leu Gly 500505 510 Lys Val Thr Met Ile Lys Thr Ala Asp Leu Lys Val Val Leu Gly 515520 525 Lys Phe Tyr Arg Asp Asp Asp Arg Asp Glu Lys Thr Ile Gln Ser 530535 540 Leu Gln Ile Ser Ala Ile Ile Leu His Pro Asn Tyr Asp Pro Ile 545550 555 Leu Leu Asp Ala Asp Ile Ala Ile Leu Lys Leu Leu Asp Lys Ala 560565 570 Arg Ile Ser Thr Arg Val Gln Pro Ile Cys Leu Ala Ala Ser Arg 575580 585 Asp Leu Ser Thr Ser Phe Gln Glu Ser His Ile Thr Val Ala Gly 590595 600 Trp Asn Val Leu Ala Asp Val Arg Ser Pro Gly Phe Lys Asn Asp 605610 615 Thr Leu Arg Ser Gly Val Val Ser Val Val Asp Ser Leu Leu Cys 620625 630 Glu Glu Gln His Glu Asp His Gly Ile Pro Val Ser Val Thr Asp 635640 645 Asn Met Phe Cys Ala Ser Trp Glu Pro Thr Ala Pro Ser Asp Ile 650655 660 Cys Thr Ala Glu Thr Gly Gly Ile Ala Ala Val Ser Phe Pro Gly 665670 675 Arg Ala Ser Pro Glu Pro Arg Trp His Leu Met Gly Leu Val Ser 680685 690 Trp Ser Tyr Asp Lys Thr Cys Ser His Arg Leu Ser Thr Ala Phe 695700 705 Thr Lys Val Leu Pro Phe Lys Asp Trp Ile Glu Arg Asn Met Lys 710715 720 39 2571 DNA Homo Sapien 39 ggttcctaca tcctctcatc tgagaatcagagagcataat cttcttacgg 50 gcccgtgatt tattaacgtg gcttaatctg aaggttctcagtcaaattct 100 ttgtgatcta ctgattgtgg gggcatggca aggtttgctt aaaggagctt150 ggctggtttg ggcccttgta gctgacagaa ggtggccagg gagaatgcag 200cacactgctc ggagaatgaa ggcgcttctg ttgctggtct tgccttggct 250 cagtcctgctaactacattg acaatgtggg caacctgcac ttcctgtatt 300 cagaactctg taaaggtgcctcccactacg gcctgaccaa agataggaag 350 aggcgctcac aagatggctg tccagacggctgtgcgagcc tcacagccac 400 ggctccctcc ccagaggttt ctgcagctgc caccatctccttaatgacag 450 acgagcctgg cctagacaac cctgcctacg tgtcctcggc agaggacggg500 cagccagcaa tcagcccagt ggactctggc cggagcaacc gaactagggc 550acggcccttt gagagatcca ctattagaag cagatcattt aaaaaaataa 600 atcgagctttgagtgttctt cgaaggacaa agagcgggag tgcagttgcc 650 aaccatgccg accagggcagggaaaattct gaaaacacca ctgcccctga 700 agtctttcca aggttgtacc acctgattccagatggtgaa attaccagca 750 tcaagatcaa tcgagtagat cccagtgaaa gcctctctattaggctggtg 800 ggaggtagcg aaaccccact ggtccatatc attatccaac acatttatcg850 tgatggggtg atcgccagag acggccggct actgccagga gacatcattc 900taaaggtcaa cgggatggac atcagcaatg tccctcacaa ctacgctgtg 950 cgtctcctgcggcagccctg ccaggtgctg tggctgactg tgatgcgtga 1000 acagaagttc cgcagcaggaacaatggaca ggccccggat gcctacagac 1050 cccgagatga cagctttcat gtgattctcaacaaaagtag ccccgaggag 1100 cagcttggaa taaaactggt gcgcaaggtg gatgagcctggggttttcat 1150 cttcaatgtg ctggatggcg gtgtggcata tcgacatggt cagcttgagg1200 agaatgaccg tgtgttagcc atcaatggac atgatcttcg atatggcagc 1250ccagaaagtg cggctcatct gattcaggcc agtgaaagac gtgttcacct 1300 cgtcgtgtcccgccaggttc ggcagcggag ccctgacatc tttcaggaag 1350 ccggctggaa cagcaatggcagctggtccc cagggccagg ggagaggagc 1400 aacactccca agcccctcca tcctacaattacttgtcatg agaaggtggt 1450 aaatatccaa aaagaccccg gtgaatctct cggcatgaccgtcgcagggg 1500 gagcatcaca tagagaatgg gatttgccta tctatgtcat cagtgttgag1550 cccggaggag tcataagcag agatggaaga ataaaaacag gtgacatttt 1600gttgaatgtg gatggggtcg aactgacaga ggtcagccgg agtgaggcag 1650 tggcattattgaaaagaaca tcatcctcga tagtactcaa agctttggaa 1700 gtcaaagagt atgagccccaggaagactgc agcagcccag cagccctgga 1750 ctccaaccac aacatggccc cacccagtgactggtcccca tcctgggtca 1800 tgtggctgga attaccacgg tgcttgtata actgtaaagatattgtatta 1850 cgaagaaaca cagctggaag tctgggcttc tgcattgtag gaggttatga1900 agaatacaat ggaaacaaac cttttttcat caaatccatt gttgaaggaa 1950caccagcata caatgatgga agaattagat gtggtgatat tcttcttgct 2000 gtcaatggtagaagtacatc aggaatgata catgcttgct tggcaagact 2050 gctgaaagaa cttaaaggaagaattactct aactattgtt tcttggcctg 2100 gcactttttt atagaatcaa tgatgggtcagaggaaaaca gaaaaatcac 2150 aaataggcta agaagttgaa acactatatt tatcttgtcagtttttatat 2200 ttaaagaaag aatacattgt aaaaatgtca ggaaaagtat gatcatctaa2250 tgaaagccag ttacacctca gaaaatatga ttccaaaaaa attaaaacta 2300ctagtttttt ttcagtgtgg aggatttctc attactctac aacattgttt 2350 atattttttctattcaataa aaagccctaa aacaactaaa atgattgatt 2400 tgtatacccc actgaattcaagctgattta aatttaaaat ttggtatatg 2450 ctgaagtctg ccaagggtac attatggccatttttaattt acagctaaaa 2500 tattttttaa aatgcattgc tgagaaacgt tgctttcatcaaacaagaat 2550 aaatattttt cagaagttaa a 2571 40 632 PRT Homo Sapien 40Met Lys Ala Leu Leu Leu Leu Val Leu Pro Trp Leu Ser Pro Ala 1 5 10 15Asn Tyr Ile Asp Asn Val Gly Asn Leu His Phe Leu Tyr Ser Glu 20 25 30 LeuCys Lys Gly Ala Ser His Tyr Gly Leu Thr Lys Asp Arg Lys 35 40 45 Arg ArgSer Gln Asp Gly Cys Pro Asp Gly Cys Ala Ser Leu Thr 50 55 60 Ala Thr AlaPro Ser Pro Glu Val Ser Ala Ala Ala Thr Ile Ser 65 70 75 Leu Met Thr AspGlu Pro Gly Leu Asp Asn Pro Ala Tyr Val Ser 80 85 90 Ser Ala Glu Asp GlyGln Pro Ala Ile Ser Pro Val Asp Ser Gly 95 100 105 Arg Ser Asn Arg ThrArg Ala Arg Pro Phe Glu Arg Ser Thr Ile 110 115 120 Arg Ser Arg Ser PheLys Lys Ile Asn Arg Ala Leu Ser Val Leu 125 130 135 Arg Arg Thr Lys SerGly Ser Ala Val Ala Asn His Ala Asp Gln 140 145 150 Gly Arg Glu Asn SerGlu Asn Thr Thr Ala Pro Glu Val Phe Pro 155 160 165 Arg Leu Tyr His LeuIle Pro Asp Gly Glu Ile Thr Ser Ile Lys 170 175 180 Ile Asn Arg Val AspPro Ser Glu Ser Leu Ser Ile Arg Leu Val 185 190 195 Gly Gly Ser Glu ThrPro Leu Val His Ile Ile Ile Gln His Ile 200 205 210 Tyr Arg Asp Gly ValIle Ala Arg Asp Gly Arg Leu Leu Pro Gly 215 220 225 Asp Ile Ile Leu LysVal Asn Gly Met Asp Ile Ser Asn Val Pro 230 235 240 His Asn Tyr Ala ValArg Leu Leu Arg Gln Pro Cys Gln Val Leu 245 250 255 Trp Leu Thr Val MetArg Glu Gln Lys Phe Arg Ser Arg Asn Asn 260 265 270 Gly Gln Ala Pro AspAla Tyr Arg Pro Arg Asp Asp Ser Phe His 275 280 285 Val Ile Leu Asn LysSer Ser Pro Glu Glu Gln Leu Gly Ile Lys 290 295 300 Leu Val Arg Lys ValAsp Glu Pro Gly Val Phe Ile Phe Asn Val 305 310 315 Leu Asp Gly Gly ValAla Tyr Arg His Gly Gln Leu Glu Glu Asn 320 325 330 Asp Arg Val Leu AlaIle Asn Gly His Asp Leu Arg Tyr Gly Ser 335 340 345 Pro Glu Ser Ala AlaHis Leu Ile Gln Ala Ser Glu Arg Arg Val 350 355 360 His Leu Val Val SerArg Gln Val Arg Gln Arg Ser Pro Asp Ile 365 370 375 Phe Gln Glu Ala GlyTrp Asn Ser Asn Gly Ser Trp Ser Pro Gly 380 385 390 Pro Gly Glu Arg SerAsn Thr Pro Lys Pro Leu His Pro Thr Ile 395 400 405 Thr Cys His Glu LysVal Val Asn Ile Gln Lys Asp Pro Gly Glu 410 415 420 Ser Leu Gly Met ThrVal Ala Gly Gly Ala Ser His Arg Glu Trp 425 430 435 Asp Leu Pro Ile TyrVal Ile Ser Val Glu Pro Gly Gly Val Ile 440 445 450 Ser Arg Asp Gly ArgIle Lys Thr Gly Asp Ile Leu Leu Asn Val 455 460 465 Asp Gly Val Glu LeuThr Glu Val Ser Arg Ser Glu Ala Val Ala 470 475 480 Leu Leu Lys Arg ThrSer Ser Ser Ile Val Leu Lys Ala Leu Glu 485 490 495 Val Lys Glu Tyr GluPro Gln Glu Asp Cys Ser Ser Pro Ala Ala 500 505 510 Leu Asp Ser Asn HisAsn Met Ala Pro Pro Ser Asp Trp Ser Pro 515 520 525 Ser Trp Val Met TrpLeu Glu Leu Pro Arg Cys Leu Tyr Asn Cys 530 535 540 Lys Asp Ile Val LeuArg Arg Asn Thr Ala Gly Ser Leu Gly Phe 545 550 555 Cys Ile Val Gly GlyTyr Glu Glu Tyr Asn Gly Asn Lys Pro Phe 560 565 570 Phe Ile Lys Ser IleVal Glu Gly Thr Pro Ala Tyr Asn Asp Gly 575 580 585 Arg Ile Arg Cys GlyAsp Ile Leu Leu Ala Val Asn Gly Arg Ser 590 595 600 Thr Ser Gly Met IleHis Ala Cys Leu Ala Arg Leu Leu Lys Glu 605 610 615 Leu Lys Gly Arg IleThr Leu Thr Ile Val Ser Trp Pro Gly Thr 620 625 630 Phe Leu 41 1964 DNAHomo Sapien 41 accaggcatt gtatcttcag ttgtcatcaa gttcgcaatc agattggaaa 50agctcaactt gaagctttct tgcctgcagt gaagcagaga gatagatatt 100 attcacgtaataaaaaacat gggcttcaac ctgactttcc acctttccta 150 caaattccga ttactgttgctgttgacttt gtgcctgaca gtggttgggt 200 gggccaccag taactacttc gtgggtgccattcaagagat tcctaaagca 250 aaggagttca tggctaattt ccataagacc ctcattttggggaagggaaa 300 aactctgact aatgaagcat ccacgaagaa ggtagaactt gacaactgtc350 cttctgtgtc tccttacctc agaggccaga gcaagctcat tttcaaacca 400gatctcactt tggaagaggt acaggcagaa aatcccaaag tgtccagagg 450 ccggtatcgccctcaggaat gtaaagcttt acagagggtc gccatcctcg 500 ttccccaccg gaacagagagaaacacctga tgtacctgct ggaacatctg 550 catcccttcc tgcagaggca gcagctggattatggcatct acgtcatcca 600 ccaggctgaa ggtaaaaagt ttaatcgagc caaactcttgaatgtgggct 650 atctagaagc cctcaaggaa gaaaattggg actgctttat attccacgat700 gtggacctgg tacccgagaa tgactttaac ctttacaagt gtgaggagca 750tcccaagcat ctggtggttg gcaggaacag cactgggtac aggttacgtt 800 acagtggatattttgggggt gttactgccc taagcagaga gcagtttttc 850 aaggtgaatg gattctctaacaactactgg ggatggggag gcgaagacga 900 tgacctcaga ctcagggttg agctccaaagaatgaaaatt tcccggcccc 950 tgcctgaagt gggtaaatat acaatggtct tccacactagagacaaaggc 1000 aatgaggtga acgcagaacg gatgaagctc ttacaccaag tgtcacgagt1050 ctggagaaca gatgggttga gtagttgttc ttataaatta gtatctgtgg 1100aacacaatcc tttatatatc aacatcacag tggatttctg gtttggtgca 1150 tgaccctggatcttttggtg atgtttggaa gaactgattc tttgtttgca 1200 ataattttgg cctagagacttcaaatagta gcacacatta agaacctgtt 1250 acagctcatt gttgagctga atttttcctttttgtatttt cttagcagag 1300 ctcctggtga tgtagagtat aaaacagttg taacaagacagctttcttag 1350 tcattttgat catgagggtt aaatattgta atatggatac ttgaaggact1400 ttatataaaa ggatgactca aaggataaaa tgaacgctat ttgaggactc 1450tggttgaagg agatttattt aaatttgaag taatatatta tgggataaaa 1500 ggccacaggaaataagactg ctgaatgtct gagagaacca gagttgttct 1550 cgtccaaggt agaaaggtacgaagatacaa tactgttatt catttatcct 1600 gtacaatcat ctgtgaagtg gtggtgtcaggtgagaaggc gtccacaaaa 1650 gaggggagaa aaggcgacga atcaggacac agtgaacttgggaatgaaga 1700 ggtagcagga gggtggagtg tcggctgcaa aggcagcagt agctgagctg1750 gttgcaggtg ctgatagcct tcaggggagg acctgcccag gtatgccttc 1800cagtgatgcc caccagagaa tacattctct attagttttt aaagagtttt 1850 tgtaaaatgattttgtacaa gtaggatatg aattagcagt ttacaagttt 1900 acatattaac taataataaatatgtctatc aaatacctct gtagtaaaat 1950 gtgaaaaagc aaaa 1964 42 344 PRTHomo Sapien 42 Met Gly Phe Asn Leu Thr Phe His Leu Ser Tyr Lys Phe ArgLeu 1 5 10 15 Leu Leu Leu Leu Thr Leu Cys Leu Thr Val Val Gly Trp AlaThr 20 25 30 Ser Asn Tyr Phe Val Gly Ala Ile Gln Glu Ile Pro Lys Ala Lys35 40 45 Glu Phe Met Ala Asn Phe His Lys Thr Leu Ile Leu Gly Lys Gly 5055 60 Lys Thr Leu Thr Asn Glu Ala Ser Thr Lys Lys Val Glu Leu Asp 65 7075 Asn Cys Pro Ser Val Ser Pro Tyr Leu Arg Gly Gln Ser Lys Leu 80 85 90Ile Phe Lys Pro Asp Leu Thr Leu Glu Glu Val Gln Ala Glu Asn 95 100 105Pro Lys Val Ser Arg Gly Arg Tyr Arg Pro Gln Glu Cys Lys Ala 110 115 120Leu Gln Arg Val Ala Ile Leu Val Pro His Arg Asn Arg Glu Lys 125 130 135His Leu Met Tyr Leu Leu Glu His Leu His Pro Phe Leu Gln Arg 140 145 150Gln Gln Leu Asp Tyr Gly Ile Tyr Val Ile His Gln Ala Glu Gly 155 160 165Lys Lys Phe Asn Arg Ala Lys Leu Leu Asn Val Gly Tyr Leu Glu 170 175 180Ala Leu Lys Glu Glu Asn Trp Asp Cys Phe Ile Phe His Asp Val 185 190 195Asp Leu Val Pro Glu Asn Asp Phe Asn Leu Tyr Lys Cys Glu Glu 200 205 210His Pro Lys His Leu Val Val Gly Arg Asn Ser Thr Gly Tyr Arg 215 220 225Leu Arg Tyr Ser Gly Tyr Phe Gly Gly Val Thr Ala Leu Ser Arg 230 235 240Glu Gln Phe Phe Lys Val Asn Gly Phe Ser Asn Asn Tyr Trp Gly 245 250 255Trp Gly Gly Glu Asp Asp Asp Leu Arg Leu Arg Val Glu Leu Gln 260 265 270Arg Met Lys Ile Ser Arg Pro Leu Pro Glu Val Gly Lys Tyr Thr 275 280 285Met Val Phe His Thr Arg Asp Lys Gly Asn Glu Val Asn Ala Glu 290 295 300Arg Met Lys Leu Leu His Gln Val Ser Arg Val Trp Arg Thr Asp 305 310 315Gly Leu Ser Ser Cys Ser Tyr Lys Leu Val Ser Val Glu His Asn 320 325 330Pro Leu Tyr Ile Asn Ile Thr Val Asp Phe Trp Phe Gly Ala 335 340 43 485DNA Homo Sapien 43 gctcaagacc cagcagtggg acagccagac agacggcacgatggcactga 50 gctcccagat ctgggccgct tgcctcctgc tcctcctcct cctcgccagc 100ctgaccagtg gctctgtttt cccacaacag acgggacaac ttgcagagct 150 gcaaccccaggacagagctg gagccagggc cagctggatg cccatgttcc 200 agaggcgaag gaggcgagacacccacttcc ccatctgcat tttctgctgc 250 ggctgctgtc atcgatcaaa gtgtgggatgtgctgcaaga cgtagaacct 300 acctgccctg cccccgtccc ctcccttcct tatttattcctgctgcccca 350 gaacataggt cttggaataa aatggctggt tcttttgttt tccaaaaaaa400 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 450aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaa 485 44 84 PRT Homo Sapien 44 MetAla Leu Ser Ser Gln Ile Trp Ala Ala Cys Leu Leu Leu Leu 1 5 10 15 LeuLeu Leu Ala Ser Leu Thr Ser Gly Ser Val Phe Pro Gln Gln 20 25 30 Thr GlyGln Leu Ala Glu Leu Gln Pro Gln Asp Arg Ala Gly Ala 35 40 45 Arg Ala SerTrp Met Pro Met Phe Gln Arg Arg Arg Arg Arg Asp 50 55 60 Thr His Phe ProIle Cys Ile Phe Cys Cys Gly Cys Cys His Arg 65 70 75 Ser Lys Cys Gly MetCys Cys Lys Thr 80 45 1076 DNA Homo Sapien 45 gtggcttcat ttcagtggctgacttccaga gagcaatatg gctggttccc 50 caacatgcct caccctcatc tatatcctttggcagctcac agggtcagca 100 gcctctggac ccgtgaaaga gctggtcggt tccgttggtggggccgtgac 150 tttccccctg aagtccaaag taaagcaagt tgactctatt gtctggacct200 tcaacacaac ccctcttgtc accatacagc cagaaggggg cactatcata 250gtgacccaaa atcgtaatag ggagagagta gacttcccag atggaggcta 300 ctccctgaagctcagcaaac tgaagaagaa tgactcaggg atctactatg 350 tggggatata cagctcatcactccagcagc cctccaccca ggagtacgtg 400 ctgcatgtct acgagcacct gtcaaagcctaaagtcacca tgggtctgca 450 gagcaataag aatggcacct gtgtgaccaa tctgacatgctgcatggaac 500 atggggaaga ggatgtgatt tatacctgga aggccctggg gcaagcagcc550 aatgagtccc ataatgggtc catcctcccc atctcctgga gatggggaga 600aagtgatatg accttcatct gcgttgccag gaaccctgtc agcagaaact 650 tctcaagccccatccttgcc aggaagctct gtgaaggtgc tgctgatgac 700 ccagattcct ccatggtcctcctgtgtctc ctgttggtgc ccctcctgct 750 cagtctcttt gtactggggc tatttctttggtttctgaag agagagagac 800 aagaagagta cattgaagag aagaagagag tggacatttgtcgggaaact 850 cctaacatat gcccccattc tggagagaac acagagtacg acacaatccc900 tcacactaat agaacaatcc taaaggaaga tccagcaaat acggtttact 950ccactgtgga aataccgaaa aagatggaaa atccccactc actgctcacg 1000 atgccagacacaccaaggct atttgcctat gagaatgtta tctagacagc 1050 agtgcactcc cctaagtctctgctca 1076 46 335 PRT Homo Sapien 46 Met Ala Gly Ser Pro Thr Cys LeuThr Leu Ile Tyr Ile Leu Trp 1 5 10 15 Gln Leu Thr Gly Ser Ala Ala SerGly Pro Val Lys Glu Leu Val 20 25 30 Gly Ser Val Gly Gly Ala Val Thr PhePro Leu Lys Ser Lys Val 35 40 45 Lys Gln Val Asp Ser Ile Val Trp Thr PheAsn Thr Thr Pro Leu 50 55 60 Val Thr Ile Gln Pro Glu Gly Gly Thr Ile IleVal Thr Gln Asn 65 70 75 Arg Asn Arg Glu Arg Val Asp Phe Pro Asp Gly GlyTyr Ser Leu 80 85 90 Lys Leu Ser Lys Leu Lys Lys Asn Asp Ser Gly Ile TyrTyr Val 95 100 105 Gly Ile Tyr Ser Ser Ser Leu Gln Gln Pro Ser Thr GlnGlu Tyr 110 115 120 Val Leu His Val Tyr Glu His Leu Ser Lys Pro Lys ValThr Met 125 130 135 Gly Leu Gln Ser Asn Lys Asn Gly Thr Cys Val Thr AsnLeu Thr 140 145 150 Cys Cys Met Glu His Gly Glu Glu Asp Val Ile Tyr ThrTrp Lys 155 160 165 Ala Leu Gly Gln Ala Ala Asn Glu Ser His Asn Gly SerIle Leu 170 175 180 Pro Ile Ser Trp Arg Trp Gly Glu Ser Asp Met Thr PheIle Cys 185 190 195 Val Ala Arg Asn Pro Val Ser Arg Asn Phe Ser Ser ProIle Leu 200 205 210 Ala Arg Lys Leu Cys Glu Gly Ala Ala Asp Asp Pro AspSer Ser 215 220 225 Met Val Leu Leu Cys Leu Leu Leu Val Pro Leu Leu LeuSer Leu 230 235 240 Phe Val Leu Gly Leu Phe Leu Trp Phe Leu Lys Arg GluArg Gln 245 250 255 Glu Glu Tyr Ile Glu Glu Lys Lys Arg Val Asp Ile CysArg Glu 260 265 270 Thr Pro Asn Ile Cys Pro His Ser Gly Glu Asn Thr GluTyr Asp 275 280 285 Thr Ile Pro His Thr Asn Arg Thr Ile Leu Lys Glu AspPro Ala 290 295 300 Asn Thr Val Tyr Ser Thr Val Glu Ile Pro Lys Lys MetGlu Asn 305 310 315 Pro His Ser Leu Leu Thr Met Pro Asp Thr Pro Arg LeuPhe Ala 320 325 330 Tyr Glu Asn Val Ile 335 47 766 DNA Homo Sapien 47ggctcgagcg tttctgagcc aggggtgacc atgacctgct gcgaaggatg 50 gacatcctgcaatggattca gcctgctggt tctactgctg ttaggagtag 100 ttctcaatgc gatacctctaattgtcagct tagttgagga agaccaattt 150 tctcaaaacc ccatctcttg ctttgagtggtggttcccag gaattatagg 200 agcaggtctg atggccattc cagcaacaac aatgtccttgacagcaagaa 250 aaagagcgtg ctgcaacaac agaactggaa tgtttctttc atcatttttc300 agtgtgatca cagtcattgg tgctctgtat tgcatgctga tatccatcca 350ggctctctta aaaggtcctc tcatgtgtaa ttctccaagc aacagtaatg 400 ccaattgtgaattttcattg aaaaacatca gtgacattca tccagaatcc 450 ttcaacttgc agtggtttttcaatgactct tgtgcacctc ctactggttt 500 caataaaccc accagtaacg acaccatggcgagtggctgg agagcatcta 550 gtttccactt cgattctgaa gaaaacaaac ataggcttatccacttctca 600 gtatttttag gtctattgct tgttggaatt ctggaggtcc tgtttgggct650 cagtcagata gtcatcggtt tccttggctg tctgtgtgga gtctctaagc 700gaagaagtca aattgtgtag tttaatggga ataaaatgta agtatcagta 750 gtttgaaaaaaaaaaa 766 48 229 PRT Homo Sapien 48 Met Thr Cys Cys Glu Gly Trp Thr SerCys Asn Gly Phe Ser Leu 1 5 10 15 Leu Val Leu Leu Leu Leu Gly Val ValLeu Asn Ala Ile Pro Leu 20 25 30 Ile Val Ser Leu Val Glu Glu Asp Gln PheSer Gln Asn Pro Ile 35 40 45 Ser Cys Phe Glu Trp Trp Phe Pro Gly Ile IleGly Ala Gly Leu 50 55 60 Met Ala Ile Pro Ala Thr Thr Met Ser Leu Thr AlaArg Lys Arg 65 70 75 Ala Cys Cys Asn Asn Arg Thr Gly Met Phe Leu Ser SerPhe Phe 80 85 90 Ser Val Ile Thr Val Ile Gly Ala Leu Tyr Cys Met Leu IleSer 95 100 105 Ile Gln Ala Leu Leu Lys Gly Pro Leu Met Cys Asn Ser ProSer 110 115 120 Asn Ser Asn Ala Asn Cys Glu Phe Ser Leu Lys Asn Ile SerAsp 125 130 135 Ile His Pro Glu Ser Phe Asn Leu Gln Trp Phe Phe Asn AspSer 140 145 150 Cys Ala Pro Pro Thr Gly Phe Asn Lys Pro Thr Ser Asn AspThr 155 160 165 Met Ala Ser Gly Trp Arg Ala Ser Ser Phe His Phe Asp SerGlu 170 175 180 Glu Asn Lys His Arg Leu Ile His Phe Ser Val Phe Leu GlyLeu 185 190 195 Leu Leu Val Gly Ile Leu Glu Val Leu Phe Gly Leu Ser GlnIle 200 205 210 Val Ile Gly Phe Leu Gly Cys Leu Cys Gly Val Ser Lys ArgArg 215 220 225 Ser Gln Ile Val 49 636 DNA Homo Sapien 49 atccgttctctgcgctgcca gctcaggtga gccctcgcca aggtgacctc 50 gcaggacact ggtgaaggagcagtgaggaa cctgcagagt cacacagttg 100 ctgaccaatt gagctgtgag cctggagcagatccgtgggc tgcagacccc 150 cgccccagtg cctctccccc tgcagccctg cccctcgaactgtgacatgg 200 agagagtgac cctggccctt ctcctactgg caggcctgac tgccttggaa250 gccaatgacc catttgccaa taaagacgat cccttctact atgactggaa 300aaacctgcag ctgagcggac tgatctgcgg agggctcctg gccattgctg 350 ggatcgcggcagttctgagt ggcaaatgca aatacaagag cagccagaag 400 cagcacagtc ctgtacctgagaaggccatc ccactcatca ctccaggctc 450 tgccactact tgctgagcac aggactggcctccagggatg gcctgaagcc 500 taacactggc ccccagcacc tcctcccctg ggaggccttatcctcaagga 550 aggacttctc tccaagggca ggctgttagg cccctttctg atcaggaggc600 ttctttatga attaaactcg ccccaccacc ccctca 636 50 89 PRT Homo Sapien 50Met Glu Arg Val Thr Leu Ala Leu Leu Leu Leu Ala Gly Leu Thr 1 5 10 15Ala Leu Glu Ala Asn Asp Pro Phe Ala Asn Lys Asp Asp Pro Phe 20 25 30 TyrTyr Asp Trp Lys Asn Leu Gln Leu Ser Gly Leu Ile Cys Gly 35 40 45 Gly LeuLeu Ala Ile Ala Gly Ile Ala Ala Val Leu Ser Gly Lys 50 55 60 Cys Lys TyrLys Ser Ser Gln Lys Gln His Ser Pro Val Pro Glu 65 70 75 Lys Ala Ile ProLeu Ile Thr Pro Gly Ser Ala Thr Thr Cys 80 85 51 1734 DNA Homo Sapien 51gtggactctg agaagcccag gcagttgagg acaggagaga gaaggctgca 50 gacccagagggagggaggac agggagtcgg aaggaggagg acagaggagg 100 gcacagagac gcagagcaagggcggcaagg aggagaccct ggtgggagga 150 agacactctg gagagagagg gggctgggcagagatgaagt tccaggggcc 200 cctggcctgc ctcctgctgg ccctctgcct gggcagtggggaggctggcc 250 ccctgcagag cggagaggaa agcactggga caaatattgg ggaggccctt300 ggacatggcc tgggagacgc cctgagcgaa ggggtgggaa aggccattgg 350caaagaggcc ggaggggcag ctggctctaa agtcagtgag gcccttggcc 400 aagggaccagagaagcagtt ggcactggag tcaggcaggt tccaggcttt 450 ggcgcagcag atgctttgggcaacagggtc ggggaagcag cccatgctct 500 gggaaacact gggcacgaga ttggcagacaggcagaagat gtcattcgac 550 acggagcaga tgctgtccgc ggctcctggc agggggtgcctggccacagt 600 ggtgcttggg aaacttctgg aggccatggc atctttggct ctcaaggtgg650 ccttggaggc cagggccagg gcaatcctgg aggtctgggg actccgtggg 700tccacggata ccccggaaac tcagcaggca gctttggaat gaatcctcag 750 ggagctccctggggtcaagg aggcaatgga gggccaccaa actttgggac 800 caacactcag ggagctgtggcccagcctgg ctatggttca gtgagagcca 850 gcaaccagaa tgaagggtgc acgaatcccccaccatctgg ctcaggtgga 900 ggctccagca actctggggg aggcagcggc tcacagtcgggcagcagtgg 950 cagtggcagc aatggtgaca acaacaatgg cagcagcagt ggtggcagca1000 gcagtggcag cagcagtggc agcagcagtg gcggcagcag tggcggcagc 1050agtggtggca gcagtggcaa cagtggtggc agcagaggtg acagcggcag 1100 tgagtcctcctggggatcca gcaccggctc ctcctccggc aaccacggtg 1150 ggagcggcgg aggaaatggacataaacccg ggtgtgaaaa gccagggaat 1200 gaagcccgcg ggagcgggga atctgggattcagggcttca gaggacaggg 1250 agtttccagc aacatgaggg aaataagcaa agagggcaatcgcctccttg 1300 gaggctctgg agacaattat cgggggcaag ggtcgagctg gggcagtgga1350 ggaggtgacg ctgttggtgg agtcaatact gtgaactctg agacgtctcc 1400tgggatgttt aactttgaca ctttctggaa gaattttaaa tccaagctgg 1450 gtttcatcaactgggatgcc ataaacaagg accagagaag ctctcgcatc 1500 ccgtgacctc cagacaaggagccaccagat tggatgggag cccccacact 1550 ccctccttaa aacaccaccc tctcatcactaatctcagcc cttgcccttg 1600 aaataaacct tagctgcccc acaaaaaaaa aaaaaaaaaaaaaaaaaaaa 1650 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa1700 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaa 1734 52 440 PRT Homo Sapien52 Met Lys Phe Gln Gly Pro Leu Ala Cys Leu Leu Leu Ala Leu Cys 1 5 10 15Leu Gly Ser Gly Glu Ala Gly Pro Leu Gln Ser Gly Glu Glu Ser 20 25 30 ThrGly Thr Asn Ile Gly Glu Ala Leu Gly His Gly Leu Gly Asp 35 40 45 Ala LeuSer Glu Gly Val Gly Lys Ala Ile Gly Lys Glu Ala Gly 50 55 60 Gly Ala AlaGly Ser Lys Val Ser Glu Ala Leu Gly Gln Gly Thr 65 70 75 Arg Glu Ala ValGly Thr Gly Val Arg Gln Val Pro Gly Phe Gly 80 85 90 Ala Ala Asp Ala LeuGly Asn Arg Val Gly Glu Ala Ala His Ala 95 100 105 Leu Gly Asn Thr GlyHis Glu Ile Gly Arg Gln Ala Glu Asp Val 110 115 120 Ile Arg His Gly AlaAsp Ala Val Arg Gly Ser Trp Gln Gly Val 125 130 135 Pro Gly His Ser GlyAla Trp Glu Thr Ser Gly Gly His Gly Ile 140 145 150 Phe Gly Ser Gln GlyGly Leu Gly Gly Gln Gly Gln Gly Asn Pro 155 160 165 Gly Gly Leu Gly ThrPro Trp Val His Gly Tyr Pro Gly Asn Ser 170 175 180 Ala Gly Ser Phe GlyMet Asn Pro Gln Gly Ala Pro Trp Gly Gln 185 190 195 Gly Gly Asn Gly GlyPro Pro Asn Phe Gly Thr Asn Thr Gln Gly 200 205 210 Ala Val Ala Gln ProGly Tyr Gly Ser Val Arg Ala Ser Asn Gln 215 220 225 Asn Glu Gly Cys ThrAsn Pro Pro Pro Ser Gly Ser Gly Gly Gly 230 235 240 Ser Ser Asn Ser GlyGly Gly Ser Gly Ser Gln Ser Gly Ser Ser 245 250 255 Gly Ser Gly Ser AsnGly Asp Asn Asn Asn Gly Ser Ser Ser Gly 260 265 270 Gly Ser Ser Ser GlySer Ser Ser Gly Ser Ser Ser Gly Gly Ser 275 280 285 Ser Gly Gly Ser SerGly Gly Ser Ser Gly Asn Ser Gly Gly Ser 290 295 300 Arg Gly Asp Ser GlySer Glu Ser Ser Trp Gly Ser Ser Thr Gly 305 310 315 Ser Ser Ser Gly AsnHis Gly Gly Ser Gly Gly Gly Asn Gly His 320 325 330 Lys Pro Gly Cys GluLys Pro Gly Asn Glu Ala Arg Gly Ser Gly 335 340 345 Glu Ser Gly Ile GlnGly Phe Arg Gly Gln Gly Val Ser Ser Asn 350 355 360 Met Arg Glu Ile SerLys Glu Gly Asn Arg Leu Leu Gly Gly Ser 365 370 375 Gly Asp Asn Tyr ArgGly Gln Gly Ser Ser Trp Gly Ser Gly Gly 380 385 390 Gly Asp Ala Val GlyGly Val Asn Thr Val Asn Ser Glu Thr Ser 395 400 405 Pro Gly Met Phe AsnPhe Asp Thr Phe Trp Lys Asn Phe Lys Ser 410 415 420 Lys Leu Gly Phe IleAsn Trp Asp Ala Ile Asn Lys Asp Gln Arg 425 430 435 Ser Ser Arg Ile Pro440 53 1676 DNA Homo Sapien 53 ggagaagagg ttgtgtggga caagctgctcccgacagaag gatgtcgctg 50 ctgagcctgc cctggctggg cctcagaccg gtggcaatgtccccatggct 100 actcctgctg ctggttgtgg gctcctggct actcgcccgc atcctggctt150 ggacctatgc cttctataac aactgccgcc ggctccagtg tttcccacag 200cccccaaaac ggaactggtt ttggggtcac ctgggcctga tcactcctac 250 agaggagggcttgaaggact cgacccagat gtcggccacc tattcccagg 300 gctttacggt atggctgggtcccatcatcc ccttcatcgt tttatgccac 350 cctgacacca tccggtctat caccaatgcctcagctgcca ttgcacccaa 400 ggataatctc ttcatcaggt tcctgaagcc ctggctgggagaagggatac 450 tgctgagtgg cggtgacaag tggagccgcc accgtcggat gctgacgccc500 gccttccatt tcaacatcct gaagtcctat ataacgatct tcaacaagag 550tgcaaacatc atgcttgaca agtggcagca cctggcctca gagggcagca 600 gtcgtctggacatgtttgag cacatcagcc tcatgacctt ggacagtcta 650 cagaaatgca tcttcagctttgacagccat tgtcaggaga ggcccagtga 700 atatattgcc accatcttgg agctcagtgcccttgtagag aaaagaagcc 750 agcatatcct ccagcacatg gactttctgt attacctctcccatgacggg 800 cggcgcttcc acagggcctg ccgcctggtg catgacttca cagacgctgt850 catccgggag cggcgtcgca ccctccccac tcagggtatt gatgattttt 900tcaaagacaa agccaagtcc aagactttgg atttcattga tgtgcttctg 950 ctgagcaaggatgaagatgg gaaggcattg tcagatgagg atataagagc 1000 agaggctgac accttcatgtttggaggcca tgacaccacg gccagtggcc 1050 tctcctgggt cctgtacaac cttgcgaggcacccagaata ccaggagcgc 1100 tgccgacagg aggtgcaaga gcttctgaag gaccgcgatcctaaagagat 1150 tgaatgggac gacctggccc agctgccctt cctgaccatg tgcgtgaagg1200 agagcctgag gttacatccc ccagctccct tcatctcccg atgctgcacc 1250caggacattg ttctcccaga tggccgagtc atccccaaag gcattacctg 1300 cctcatcgatattatagggg tccatcacaa cccaactgtg tggccggatc 1350 ctgaggtcta cgaccccttccgctttgacc cagagaacag caaggggagg 1400 tcacctctgg cttttattcc tttctccgcagggcccagga actgcatcgg 1450 gcaggcgttc gccatggcgg agatgaaagt ggtcctggcgttgatgctgc 1500 tgcacttccg gttcctgcca gaccacactg agccccgcag gaagctggaa1550 ttgatcatgc gcgccgaggg cgggctttgg ctgcgggtgg agcccctgaa 1600tgtaggcttg cagtgacttt ctgacccatc cacctgtttt tttgcagatt 1650 gtcatgaataaaacggtgct gtcaaa 1676 54 524 PRT Homo Sapien 54 Met Ser Leu Leu Ser LeuPro Trp Leu Gly Leu Arg Pro Val Ala 1 5 10 15 Met Ser Pro Trp Leu LeuLeu Leu Leu Val Val Gly Ser Trp Leu 20 25 30 Leu Ala Arg Ile Leu Ala TrpThr Tyr Ala Phe Tyr Asn Asn Cys 35 40 45 Arg Arg Leu Gln Cys Phe Pro GlnPro Pro Lys Arg Asn Trp Phe 50 55 60 Trp Gly His Leu Gly Leu Ile Thr ProThr Glu Glu Gly Leu Lys 65 70 75 Asp Ser Thr Gln Met Ser Ala Thr Tyr SerGln Gly Phe Thr Val 80 85 90 Trp Leu Gly Pro Ile Ile Pro Phe Ile Val LeuCys His Pro Asp 95 100 105 Thr Ile Arg Ser Ile Thr Asn Ala Ser Ala AlaIle Ala Pro Lys 110 115 120 Asp Asn Leu Phe Ile Arg Phe Leu Lys Pro TrpLeu Gly Glu Gly 125 130 135 Ile Leu Leu Ser Gly Gly Asp Lys Trp Ser ArgHis Arg Arg Met 140 145 150 Leu Thr Pro Ala Phe His Phe Asn Ile Leu LysSer Tyr Ile Thr 155 160 165 Ile Phe Asn Lys Ser Ala Asn Ile Met Leu AspLys Trp Gln His 170 175 180 Leu Ala Ser Glu Gly Ser Ser Arg Leu Asp MetPhe Glu His Ile 185 190 195 Ser Leu Met Thr Leu Asp Ser Leu Gln Lys CysIle Phe Ser Phe 200 205 210 Asp Ser His Cys Gln Glu Arg Pro Ser Glu TyrIle Ala Thr Ile 215 220 225 Leu Glu Leu Ser Ala Leu Val Glu Lys Arg SerGln His Ile Leu 230 235 240 Gln His Met Asp Phe Leu Tyr Tyr Leu Ser HisAsp Gly Arg Arg 245 250 255 Phe His Arg Ala Cys Arg Leu Val His Asp PheThr Asp Ala Val 260 265 270 Ile Arg Glu Arg Arg Arg Thr Leu Pro Thr GlnGly Ile Asp Asp 275 280 285 Phe Phe Lys Asp Lys Ala Lys Ser Lys Thr LeuAsp Phe Ile Asp 290 295 300 Val Leu Leu Leu Ser Lys Asp Glu Asp Gly LysAla Leu Ser Asp 305 310 315 Glu Asp Ile Arg Ala Glu Ala Asp Thr Phe MetPhe Gly Gly His 320 325 330 Asp Thr Thr Ala Ser Gly Leu Ser Trp Val LeuTyr Asn Leu Ala 335 340 345 Arg His Pro Glu Tyr Gln Glu Arg Cys Arg GlnGlu Val Gln Glu 350 355 360 Leu Leu Lys Asp Arg Asp Pro Lys Glu Ile GluTrp Asp Asp Leu 365 370 375 Ala Gln Leu Pro Phe Leu Thr Met Cys Val LysGlu Ser Leu Arg 380 385 390 Leu His Pro Pro Ala Pro Phe Ile Ser Arg CysCys Thr Gln Asp 395 400 405 Ile Val Leu Pro Asp Gly Arg Val Ile Pro LysGly Ile Thr Cys 410 415 420 Leu Ile Asp Ile Ile Gly Val His His Asn ProThr Val Trp Pro 425 430 435 Asp Pro Glu Val Tyr Asp Pro Phe Arg Phe AspPro Glu Asn Ser 440 445 450 Lys Gly Arg Ser Pro Leu Ala Phe Ile Pro PheSer Ala Gly Pro 455 460 465 Arg Asn Cys Ile Gly Gln Ala Phe Ala Met AlaGlu Met Lys Val 470 475 480 Val Leu Ala Leu Met Leu Leu His Phe Arg PheLeu Pro Asp His 485 490 495 Thr Glu Pro Arg Arg Lys Leu Glu Leu Ile MetArg Ala Glu Gly 500 505 510 Gly Leu Trp Leu Arg Val Glu Pro Leu Asn ValGly Leu Gln 515 520 55 644 DNA Homo Sapien 55 atcgcatcaa ttgggagtaccatcttcctc atgggaccag tgaaacagct 50 gaagcgaatg tttgagccta ctcgtttgattgcaactatc atggtgctgt 100 tgtgttttgc acttaccctg tgttctgcct tttggtggcataacaaggga 150 cttgcactta tcttctgcat tttgcagtct ttggcattga cgtggtacag200 cctttccttc ataccatttg caagggatgc tgtgaagaag tgttttgccg 250tgtgtcttgc ataattcatg gccagtttta tgaagctttg gaaggcacta 300 tggacagaagctggtggaca gttttgtaac tatcttcgaa acctctgtct 350 tacagacatg tgccttttatcttgcagcaa tgtgttgctt gtgattcgaa 400 catttgaggg ttacttttgg aagcaacaatacattctcga acctgaatgt 450 cagtagcaca ggatgagaag tgggttctgt atcttgtggagtggaatctt 500 cctcatgtac ctgtttcctc tctggatgtt gtcccactga attcccatga550 atacaaacct attcagcaac agcaaaaaaa aaaaaaaaaa aaaaaaaaaa 600aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaa 644 56 77 PRT HomoSapien 56 Met Gly Pro Val Lys Gln Leu Lys Arg Met Phe Glu Pro Thr Arg 15 10 15 Leu Ile Ala Thr Ile Met Val Leu Leu Cys Phe Ala Leu Thr Leu 2025 30 Cys Ser Ala Phe Trp Trp His Asn Lys Gly Leu Ala Leu Ile Phe 35 4045 Cys Ile Leu Gln Ser Leu Ala Leu Thr Trp Tyr Ser Leu Ser Phe 50 55 60Ile Pro Phe Ala Arg Asp Ala Val Lys Lys Cys Phe Ala Val Cys 65 70 75 LeuAla 57 3334 DNA Homo Sapien 57 cggctcgagc tcgagccgaa tcggctcgaggggcagtgga gcacccagca 50 ggccgccaac atgctctgtc tgtgcctgta cgtgccggtcatcggggaag 100 cccagaccga gttccagtac tttgagtcga aggggctccc tgccgagctg150 aagtccattt tcaagctcag tgtcttcatc ccctcccagg aattctccac 200ctaccgccag tggaagcaga aaattgtaca agctggagat aaggaccttg 250 atgggcagctagactttgaa gaatttgtcc attatctcca agatcatgag 300 aagaagctga ggctggtgtttaagattttg gacaaaaaga atgatggacg 350 cattgacgcg caggagatca tgcagtccctgcgggacttg ggagtcaaga 400 tatctgaaca gcaggcagaa aaaattctca agagcatggataaaaacggc 450 acgatgacca tcgactggaa cgagtggaga gactaccacc tcctccaccc500 cgtggaaaac atccccgaga tcatcctcta ctggaagcat tccacgatct 550ttgatgtggg tgagaatcta acggtcccgg atgagttcac agtggaggag 600 aggcagacggggatgtggtg gagacacctg gtggcaggag gtggggcagg 650 ggccgtatcc agaacctgcacggcccccct ggacaggctc aaggtgctca 700 tgcaggtcca tgcctcccgc agcaacaacatgggcatcgt tggtggcttc 750 actcagatga ttcgagaagg aggggccagg tcactctggcggggcaatgg 800 catcaacgtc ctcaaaattg cccccgaatc agccatcaaa ttcatggcct850 atgagcagat caagcgcctt gttggtagtg accaggagac tctgaggatt 900cacgagaggc ttgtggcagg gtccttggca ggggccatcg cccagagcag 950 catctacccaatggaggtcc tgaagacccg gatggcgctg cggaagacag 1000 gccagtactc aggaatgctggactgcgcca ggaggatcct ggccagagag 1050 ggggtggccg ccttctacaa aggctatgtccccaacatgc tgggcatcat 1100 cccctatgcc ggcatcgacc ttgcagtcta cgagacgctcaagaatgcct 1150 ggctgcagca ctatgcagtg aacagcgcgg accccggcgt gtttgtgctc1200 ctggcctgtg gcaccatgtc cagtacctgt ggccagctgg ccagctaccc 1250cctggcccta gtcaggaccc ggatgcaggc gcaagcctct attgagggcg 1300 ctccggaggtgaccatgagc agcctcttca aacatatcct gcggaccgag 1350 ggggccttcg ggctgtacagggggctggcc cccaacttca tgaaggtcat 1400 cccagctgtg agcatcagct acgtggtctacgagaacctg aagatcaccc 1450 tgggcgtgca gtcgcggtga cggggggagg gccgcccggcagtggactcg 1500 ctgatcctgg gccgcagcct ggggtgtgca gccatctcat tctgtgaatg1550 tgccaacact aagctgtctc gagccaagct gtgaaaaccc tagacgcacc 1600cgcagggagg gtggggagag ctggcaggcc cagggcttgt cctgctgacc 1650 ccagcagaccctcctgttgg ttccagcgaa gaccacaggc attccttagg 1700 gtccagggtc agcaggctccgggctcacat gtgtaaggac aggacatttt 1750 ctgcagtgcc tgccaatagt gagcttggagcctggaggcc ggcttagttc 1800 ttccatttca cccttgcagc cagctgttgg ccacggcccctgccctctgg 1850 tctgccgtgc atctccctgt gccctcttgc tgcctgcctg tctgctgagg1900 taaggtggga ggagggctac agcccacatc ccaccccctc gtccaatccc 1950ataatccatg atgaaaggtg aggtcacgtg gcctcccagg cctgacttcc 2000 caacctacagcattgacgcc aacttggctg tgaaggaaga ggaaaggatc 2050 tggccttgtg gtcactggcatctgagccct gctgatggct ggggctctcg 2100 ggcatgcttg ggagtgcagg gggctcgggctgcctggcct ggctgcacag 2150 aaggcaagtg ctggggctca tggtgctctg agctggcctggaccctgtca 2200 ggatgggccc cacctcagaa ccaaactcac tgtccccact gtggcatgag2250 ggcagtggag caccatgttt gagggcgaag ggcagagcgt ttgtgtgttc 2300tggggaggga aggaaaaggt gttggaggcc ttaattatgg actgttggga 2350 aaagggttttgtccagaagg acaagccgga caaatgagcg acttctgtgc 2400 ttccagagga agacgagggagcaggagctt ggctgactgc tcagagtctg 2450 ttctgacgcc ctgggggttc ctgtccaaccccagcagggg cgcagcggga 2500 ccagccccac attccacttg tgtcactgct tggaacctatttattttgta 2550 tttatttgaa cagagttatg tcctaactat ttttatagat ttgtttaatt2600 aatagcttgt cattttcaag ttcatttttt attcatattt atgttcatgg 2650ttgattgtac cttcccaagc ccgcccagtg ggatgggagg aggaggagaa 2700 ggggggccttgggccgctgc agtcacatct gtccagagaa attccttttg 2750 ggactggagg cagaaaagcggccagaaggc agcagccctg gctcctttcc 2800 tttggcaggt tggggaaggg cttgcccccagccttaggat ttcagggttt 2850 gactgggggc gtggagagag agggaggaac ctcaataaccttgaaggtgg 2900 aatccagtta tttcctgcgc tgcgagggtt tctttatttc actcttttct2950 gaatgtcaag gcagtgaggt gcctctcact gtgaatttgt ggtgggcggg 3000ggctggagga gagggtgggg ggctggctcc gtccctccca gccttctgct 3050 gcccttgcttaacaatgccg gccaactggc gacctcacgg ttgcacttcc 3100 attccaccag aatgacctgatgaggaaatc ttcaatagga tgcaaagatc 3150 aatgcaaaaa ttgttatata tgaacatataactggagtcg tcaaaaagca 3200 aattaagaaa gaattggacg ttagaagttg tcatttaaagcagccttcta 3250 ataaagttgt ttcaaagctg aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa3300 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaa 3334 58 469 PRT Homo Sapien58 Met Leu Cys Leu Cys Leu Tyr Val Pro Val Ile Gly Glu Ala Gln 1 5 10 15Thr Glu Phe Gln Tyr Phe Glu Ser Lys Gly Leu Pro Ala Glu Leu 20 25 30 LysSer Ile Phe Lys Leu Ser Val Phe Ile Pro Ser Gln Glu Phe 35 40 45 Ser ThrTyr Arg Gln Trp Lys Gln Lys Ile Val Gln Ala Gly Asp 50 55 60 Lys Asp LeuAsp Gly Gln Leu Asp Phe Glu Glu Phe Val His Tyr 65 70 75 Leu Gln Asp HisGlu Lys Lys Leu Arg Leu Val Phe Lys Ile Leu 80 85 90 Asp Lys Lys Asn AspGly Arg Ile Asp Ala Gln Glu Ile Met Gln 95 100 105 Ser Leu Arg Asp LeuGly Val Lys Ile Ser Glu Gln Gln Ala Glu 110 115 120 Lys Ile Leu Lys SerMet Asp Lys Asn Gly Thr Met Thr Ile Asp 125 130 135 Trp Asn Glu Trp ArgAsp Tyr His Leu Leu His Pro Val Glu Asn 140 145 150 Ile Pro Glu Ile IleLeu Tyr Trp Lys His Ser Thr Ile Phe Asp 155 160 165 Val Gly Glu Asn LeuThr Val Pro Asp Glu Phe Thr Val Glu Glu 170 175 180 Arg Gln Thr Gly MetTrp Trp Arg His Leu Val Ala Gly Gly Gly 185 190 195 Ala Gly Ala Val SerArg Thr Cys Thr Ala Pro Leu Asp Arg Leu 200 205 210 Lys Val Leu Met GlnVal His Ala Ser Arg Ser Asn Asn Met Gly 215 220 225 Ile Val Gly Gly PheThr Gln Met Ile Arg Glu Gly Gly Ala Arg 230 235 240 Ser Leu Trp Arg GlyAsn Gly Ile Asn Val Leu Lys Ile Ala Pro 245 250 255 Glu Ser Ala Ile LysPhe Met Ala Tyr Glu Gln Ile Lys Arg Leu 260 265 270 Val Gly Ser Asp GlnGlu Thr Leu Arg Ile His Glu Arg Leu Val 275 280 285 Ala Gly Ser Leu AlaGly Ala Ile Ala Gln Ser Ser Ile Tyr Pro 290 295 300 Met Glu Val Leu LysThr Arg Met Ala Leu Arg Lys Thr Gly Gln 305 310 315 Tyr Ser Gly Met LeuAsp Cys Ala Arg Arg Ile Leu Ala Arg Glu 320 325 330 Gly Val Ala Ala PheTyr Lys Gly Tyr Val Pro Asn Met Leu Gly 335 340 345 Ile Ile Pro Tyr AlaGly Ile Asp Leu Ala Val Tyr Glu Thr Leu 350 355 360 Lys Asn Ala Trp LeuGln His Tyr Ala Val Asn Ser Ala Asp Pro 365 370 375 Gly Val Phe Val LeuLeu Ala Cys Gly Thr Met Ser Ser Thr Cys 380 385 390 Gly Gln Leu Ala SerTyr Pro Leu Ala Leu Val Arg Thr Arg Met 395 400 405 Gln Ala Gln Ala SerIle Glu Gly Ala Pro Glu Val Thr Met Ser 410 415 420 Ser Leu Phe Lys HisIle Leu Arg Thr Glu Gly Ala Phe Gly Leu 425 430 435 Tyr Arg Gly Leu AlaPro Asn Phe Met Lys Val Ile Pro Ala Val 440 445 450 Ser Ile Ser Tyr ValVal Tyr Glu Asn Leu Lys Ile Thr Leu Gly 455 460 465 Val Gln Ser Arg 591658 DNA Homo Sapien 59 ggaaggcagc ggcagctcca ctcagccagt acccagatacgctgggaacc 50 ttccccagcc atggcttccc tggggcagat cctcttctgg agcataatta 100gcatcatcat tattctggct ggagcaattg cactcatcat tggctttggt 150 atttcagggagacactccat cacagtcact actgtcgcct cagctgggaa 200 cattggggag gatggaatcctgagctgcac ttttgaacct gacatcaaac 250 tttctgatat cgtgatacaa tggctgaaggaaggtgtttt aggcttggtc 300 catgagttca aagaaggcaa agatgagctg tcggagcaggatgaaatgtt 350 cagaggccgg acagcagtgt ttgctgatca agtgatagtt ggcaatgcct400 ctttgcggct gaaaaacgtg caactcacag atgctggcac ctacaaatgt 450tatatcatca cttctaaagg caaggggaat gctaaccttg agtataaaac 500 tggagccttcagcatgccgg aagtgaatgt ggactataat gccagctcag 550 agaccttgcg gtgtgaggctccccgatggt tcccccagcc cacagtggtc 600 tgggcatccc aagttgacca gggagccaacttctcggaag tctccaatac 650 cagctttgag ctgaactctg agaatgtgac catgaaggttgtgtctgtgc 700 tctacaatgt tacgatcaac aacacatact cctgtatgat tgaaaatgac750 attgccaaag caacagggga tatcaaagtg acagaatcgg agatcaaaag 800gcggagtcac ctacagctgc taaactcaaa ggcttctctg tgtgtctctt 850 ctttctttgccatcagctgg gcacttctgc ctctcagccc ttacctgatg 900 ctaaaataat gtgccttggccacaaaaaag catgcaaagt cattgttaca 950 acagggatct acagaactat ttcaccaccagatatgacct agttttatat 1000 ttctgggagg aaatgaattc atatctagaa gtctggagtgagcaaacaag 1050 agcaagaaac aaaaagaagc caaaagcaga aggctccaat atgaacaaga1100 taaatctatc ttcaaagaca tattagaagt tgggaaaata attcatgtga 1150actagacaag tgtgttaaga gtgataagta aaatgcacgt ggagacaagt 1200 gcatccccagatctcaggga cctccccctg cctgtcacct ggggagtgag 1250 aggacaggat agtgcatgttctttgtctct gaatttttag ttatatgtgc 1300 tgtaatgttg ctctgaggaa gcccctggaaagtctatccc aacatatcca 1350 catcttatat tccacaaatt aagctgtagt atgtaccctaagacgctgct 1400 aattgactgc cacttcgcaa ctcaggggcg gctgcatttt agtaatgggt1450 caaatgattc actttttatg atgcttccaa aggtgccttg gcttctcttc 1500ccaactgaca aatgccaaag ttgagaaaaa tgatcataat tttagcataa 1550 acagagcagtcggggacacc gattttataa ataaactgag caccttcttt 1600 ttaaacaaaa aaaaaaaaaaaaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 1650 aaaaaaaa 1658 60 282 PRT HomoSapien 60 Met Ala Ser Leu Gly Gln Ile Leu Phe Trp Ser Ile Ile Ser Ile 15 10 15 Ile Ile Ile Leu Ala Gly Ala Ile Ala Leu Ile Ile Gly Phe Gly 2025 30 Ile Ser Gly Arg His Ser Ile Thr Val Thr Thr Val Ala Ser Ala 35 4045 Gly Asn Ile Gly Glu Asp Gly Ile Leu Ser Cys Thr Phe Glu Pro 50 55 60Asp Ile Lys Leu Ser Asp Ile Val Ile Gln Trp Leu Lys Glu Gly 65 70 75 ValLeu Gly Leu Val His Glu Phe Lys Glu Gly Lys Asp Glu Leu 80 85 90 Ser GluGln Asp Glu Met Phe Arg Gly Arg Thr Ala Val Phe Ala 95 100 105 Asp GlnVal Ile Val Gly Asn Ala Ser Leu Arg Leu Lys Asn Val 110 115 120 Gln LeuThr Asp Ala Gly Thr Tyr Lys Cys Tyr Ile Ile Thr Ser 125 130 135 Lys GlyLys Gly Asn Ala Asn Leu Glu Tyr Lys Thr Gly Ala Phe 140 145 150 Ser MetPro Glu Val Asn Val Asp Tyr Asn Ala Ser Ser Glu Thr 155 160 165 Leu ArgCys Glu Ala Pro Arg Trp Phe Pro Gln Pro Thr Val Val 170 175 180 Trp AlaSer Gln Val Asp Gln Gly Ala Asn Phe Ser Glu Val Ser 185 190 195 Asn ThrSer Phe Glu Leu Asn Ser Glu Asn Val Thr Met Lys Val 200 205 210 Val SerVal Leu Tyr Asn Val Thr Ile Asn Asn Thr Tyr Ser Cys 215 220 225 Met IleGlu Asn Asp Ile Ala Lys Ala Thr Gly Asp Ile Lys Val 230 235 240 Thr GluSer Glu Ile Lys Arg Arg Ser His Leu Gln Leu Leu Asn 245 250 255 Ser LysAla Ser Leu Cys Val Ser Ser Phe Phe Ala Ile Ser Trp 260 265 270 Ala LeuLeu Pro Leu Ser Pro Tyr Leu Met Leu Lys 275 280 61 1617 DNA Homo Sapien61 tgacgtcaga atcaccatgg ccagctatcc ttaccggcag ggctgcccag 50 gagctgcaggacaagcacca ggagcccctc cgggtagcta ctaccctgga 100 ccccccaata gtggagggcagtatggtagt gggctacccc ctggtggtgg 150 ttatgggggt cctgcccctg gagggccttatggaccacca gctggtggag 200 ggccctatgg acaccccaat cctgggatgt tcccctctggaactccagga 250 ggaccatatg gcggtgcagc tcccgggggc ccctatggtc agccacctcc300 aagttcctac ggtgcccagc agcctgggct ttatggacag ggtggcgccc 350ctcccaatgt ggatcctgag gcctactcct ggttccagtc ggtggactca 400 gatcacagtggctatatctc catgaaggag ctaaagcagg ccctggtcaa 450 ctgcaattgg tcttcattcaatgatgagac ctgcctcatg atgataaaca 500 tgtttgacaa gaccaagtca ggccgcatcgatgtctacgg cttctcagcc 550 ctgtggaaat tcatccagca gtggaagaac ctcttccagcagtatgaccg 600 ggaccgctcg ggctccatta gctacacaga gctgcagcaa gctctgtccc650 aaatgggcta caacctgagc ccccagttca cccagcttct ggtctcccgc 700tactgcccac gctctgccaa tcctgccatg cagcttgacc gcttcatcca 750 ggtgtgcacccagctgcagg tgctgacaga ggccttccgg gagaaggaca 800 cagctgtaca aggcaacatccggctcagct tcgaggactt cgtcaccatg 850 acagcttctc ggatgctatg acccaaccatctgtggagag tggagtgcac 900 cagggacctt tcctggcttc ttagagtgag agaagtatgtggacatctct 950 tcttttcctg tccctctaga agaacattct cccttgcttg atgcaacact1000 gttccaaaag agggtggaga gtcctgcatc atagccacca aatagtgagg 1050accggggctg aggccacaca gataggggcc tgatggagga gaggatagaa 1100 gttgaatgtcctgatggcca tgagcagttg agtggcacag cctggcacca 1150 ggagcaggtc cttgtaatggagttagtgtc cagtcagctg agctccaccc 1200 tgatgccagt ggtgagtgtt catcggcctgttaccgttag tacctgtgtt 1250 ccctcaccag gccatcctgt caaacgagcc cattttctccaaagtggaat 1300 ctgaccaagc atgagagaga tctgtctatg ggaccagtgg cttggattct1350 gccacaccca taaatccttg tgtgttaact tctagctgcc tggggctggc 1400cctgctcaga caaatctgct ccctgggcat ctttggccag gcttctgccc 1450 cctgcagctgggacccctca cttgcctgcc atgctctgct cggcttcagt 1500 ctccaggaga cagtggtcacctctccctgc caatactttt tttaatttgc 1550 attttttttc atttggggcc aaaagtccagtgaaattgta agcttcaata 1600 aaaggatgaa actctga 1617 62 284 PRT HomoSapien 62 Met Ala Ser Tyr Pro Tyr Arg Gln Gly Cys Pro Gly Ala Ala Gly 15 10 15 Gln Ala Pro Gly Ala Pro Pro Gly Ser Tyr Tyr Pro Gly Pro Pro 2025 30 Asn Ser Gly Gly Gln Tyr Gly Ser Gly Leu Pro Pro Gly Gly Gly 35 4045 Tyr Gly Gly Pro Ala Pro Gly Gly Pro Tyr Gly Pro Pro Ala Gly 50 55 60Gly Gly Pro Tyr Gly His Pro Asn Pro Gly Met Phe Pro Ser Gly 65 70 75 ThrPro Gly Gly Pro Tyr Gly Gly Ala Ala Pro Gly Gly Pro Tyr 80 85 90 Gly GlnPro Pro Pro Ser Ser Tyr Gly Ala Gln Gln Pro Gly Leu 95 100 105 Tyr GlyGln Gly Gly Ala Pro Pro Asn Val Asp Pro Glu Ala Tyr 110 115 120 Ser TrpPhe Gln Ser Val Asp Ser Asp His Ser Gly Tyr Ile Ser 125 130 135 Met LysGlu Leu Lys Gln Ala Leu Val Asn Cys Asn Trp Ser Ser 140 145 150 Phe AsnAsp Glu Thr Cys Leu Met Met Ile Asn Met Phe Asp Lys 155 160 165 Thr LysSer Gly Arg Ile Asp Val Tyr Gly Phe Ser Ala Leu Trp 170 175 180 Lys PheIle Gln Gln Trp Lys Asn Leu Phe Gln Gln Tyr Asp Arg 185 190 195 Asp ArgSer Gly Ser Ile Ser Tyr Thr Glu Leu Gln Gln Ala Leu 200 205 210 Ser GlnMet Gly Tyr Asn Leu Ser Pro Gln Phe Thr Gln Leu Leu 215 220 225 Val SerArg Tyr Cys Pro Arg Ser Ala Asn Pro Ala Met Gln Leu 230 235 240 Asp ArgPhe Ile Gln Val Cys Thr Gln Leu Gln Val Leu Thr Glu 245 250 255 Ala PheArg Glu Lys Asp Thr Ala Val Gln Gly Asn Ile Arg Leu 260 265 270 Ser PheGlu Asp Phe Val Thr Met Thr Ala Ser Arg Met Leu 275 280 63 1234 DNA HomoSapien 63 caggatgcag ggccgcgtgg cagggagctg cgctcctctg ggcctgctcc 50tggtctgtct tcatctccca ggcctctttg cccggagcat cggtgttgtg 100 gaggagaaagtttcccaaaa cttcgggacc aacttgcctc agctcggaca 150 accttcctcc actggcccctctaactctga acatccgcag cccgctctgg 200 accctaggtc taatgacttg gcaagggttcctctgaagct cagcgtgcct 250 ccatcagatg gcttcccacc tgcaggaggt tctgcagtgcagaggtggcc 300 tccatcgtgg gggctgcctg ccatggattc ctggccccct gaggatcctt350 ggcagatgat ggctgctgcg gctgaggacc gcctggggga agcgctgcct 400gaagaactct cttacctctc cagtgctgcg gccctcgctc cgggcagtgg 450 ccctttgcctggggagtctt ctcccgatgc cacaggcctc tcacctgagg 500 cttcactcct ccaccaggactcggagtcca gacgactgcc ccgttctaat 550 tcactgggag ccgggggaaa aatcctttcccaacgccctc cctggtctct 600 catccacagg gttctgcctg atcacccctg gggtaccctgaatcccagtg 650 tgtcctgggg aggtggaggc cctgggactg gttggggaac gaggcccatg700 ccacaccctg agggaatctg gggtatcaat aatcaacccc caggtaccag 750ctggggaaat attaatcggt atccaggagg cagctgggga aatattaatc 800 ggtatccaggaggcagctgg gggaatatta atcggtatcc aggaggcagc 850 tgggggaata ttcatctatacccaggtatc aataacccat ttcctcctgg 900 agttctccgc cctcctggct cttcttggaacatcccagct ggcttcccta 950 atcctccaag ccctaggttg cagtggggct agagcacgatagagggaaac 1000 ccaacattgg gagttagagt cctgctcccg ccccttgctg tgtgggctca1050 atccaggccc tgttaacatg tttccagcac tatccccact tttcagtgcc 1100tcccctgctc atctccaata aaataaaagc acttatgaaa aaaaaaaaaa 1150 aaaaaaaaaaaaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 1200 aaaaaaaaaa aaaaaaaaaaaaaaaaaaaa aaaa 1234 64 325 PRT Homo Sapien 64 Met Gln Gly Arg Val AlaGly Ser Cys Ala Pro Leu Gly Leu Leu 1 5 10 15 Leu Val Cys Leu His LeuPro Gly Leu Phe Ala Arg Ser Ile Gly 20 25 30 Val Val Glu Glu Lys Val SerGln Asn Phe Gly Thr Asn Leu Pro 35 40 45 Gln Leu Gly Gln Pro Ser Ser ThrGly Pro Ser Asn Ser Glu His 50 55 60 Pro Gln Pro Ala Leu Asp Pro Arg SerAsn Asp Leu Ala Arg Val 65 70 75 Pro Leu Lys Leu Ser Val Pro Pro Ser AspGly Phe Pro Pro Ala 80 85 90 Gly Gly Ser Ala Val Gln Arg Trp Pro Pro SerTrp Gly Leu Pro 95 100 105 Ala Met Asp Ser Trp Pro Pro Glu Asp Pro TrpGln Met Met Ala 110 115 120 Ala Ala Ala Glu Asp Arg Leu Gly Glu Ala LeuPro Glu Glu Leu 125 130 135 Ser Tyr Leu Ser Ser Ala Ala Ala Leu Ala ProGly Ser Gly Pro 140 145 150 Leu Pro Gly Glu Ser Ser Pro Asp Ala Thr GlyLeu Ser Pro Glu 155 160 165 Ala Ser Leu Leu His Gln Asp Ser Glu Ser ArgArg Leu Pro Arg 170 175 180 Ser Asn Ser Leu Gly Ala Gly Gly Lys Ile LeuSer Gln Arg Pro 185 190 195 Pro Trp Ser Leu Ile His Arg Val Leu Pro AspHis Pro Trp Gly 200 205 210 Thr Leu Asn Pro Ser Val Ser Trp Gly Gly GlyGly Pro Gly Thr 215 220 225 Gly Trp Gly Thr Arg Pro Met Pro His Pro GluGly Ile Trp Gly 230 235 240 Ile Asn Asn Gln Pro Pro Gly Thr Ser Trp GlyAsn Ile Asn Arg 245 250 255 Tyr Pro Gly Gly Ser Trp Gly Asn Ile Asn ArgTyr Pro Gly Gly 260 265 270 Ser Trp Gly Asn Ile Asn Arg Tyr Pro Gly GlySer Trp Gly Asn 275 280 285 Ile His Leu Tyr Pro Gly Ile Asn Asn Pro PhePro Pro Gly Val 290 295 300 Leu Arg Pro Pro Gly Ser Ser Trp Asn Ile ProAla Gly Phe Pro 305 310 315 Asn Pro Pro Ser Pro Arg Leu Gln Trp Gly 320325 65 422 DNA Homo Sapien 65 aaggagaggc caccgggact tcagtgtctcctccatccca ggagcgcagt 50 ggccactatg gggtctgggc tgccccttgt cctcctcttgaccctccttg 100 gcagctcaca tggaacaggg ccgggtatga ctttgcaact gaagctgaag150 gagtcttttc tgacaaattc ctcctatgag tccagcttcc tggaattgct 200tgaaaagctc tgcctcctcc tccatctccc ttcagggacc agcgtcaccc 250 tccaccatgcaagatctcaa caccatgttg tctgcaacac atgacagcca 300 ttgaagcctg tgtccttcttggcccgggct tttgggccgg ggatgcagga 350 ggcaggcccc gaccctgtct ttcagcaggcccccaccctc ctgagtggca 400 ataaataaaa ttcggtatgc tg 422 66 78 PRT HomoSapien 66 Met Gly Ser Gly Leu Pro Leu Val Leu Leu Leu Thr Leu Leu Gly 15 10 15 Ser Ser His Gly Thr Gly Pro Gly Met Thr Leu Gln Leu Lys Leu 2025 30 Lys Glu Ser Phe Leu Thr Asn Ser Ser Tyr Glu Ser Ser Phe Leu 35 4045 Glu Leu Leu Glu Lys Leu Cys Leu Leu Leu His Leu Pro Ser Gly 50 55 60Thr Ser Val Thr Leu His His Ala Arg Ser Gln His His Val Val 65 70 75 CysAsn Thr 67 744 DNA Homo Sapien 67 acggaccgag ggttcgaggg agggacacggaccaggaacc tgagctaggt 50 caaagacgcc cgggccaggt gccccgtcgc aggtgcccctggccggagat 100 gcggtaggag gggcgagcgc gagaagcccc ttcctcggcg ctgccaaccc150 gccacccagc ccatggcgaa ccccgggctg gggctgcttc tggcgctggg 200cctgccgttc ctgctggccc gctggggccg agcctggggg caaatacaga 250 ccacttctgcaaatgagaat agcactgttt tgccttcatc caccagctcc 300 agctccgatg gcaacctgcgtccggaagcc atcactgcta tcatcgtggt 350 cttctccctc ttggctgcct tgctcctggctgtggggctg gcactgttgg 400 tgcggaagct tcgggagaag cggcagacgg agggcacctaccggcccagt 450 agcgaggagc agttctccca tgcagccgag gcccgggccc ctcaggactc500 caaggagacg gtgcagggct gcctgcccat ctaggtcccc tctcctgcat 550ctgtctccct tcattgctgt gtgaccttgg ggaaaggcag tgccctctct 600 gggcagtcagatccacccag tgcttaatag cagggaagaa ggtacttcaa 650 agactctgcc cctgaggtcaagagaggatg gggctattca cttttatata 700 tttatataaa attagtagtg agatgtaaaaaaaaaaaaaa aaaa 744 68 123 PRT Homo Sapien 68 Met Ala Asn Pro Gly LeuGly Leu Leu Leu Ala Leu Gly Leu Pro 1 5 10 15 Phe Leu Leu Ala Arg TrpGly Arg Ala Trp Gly Gln Ile Gln Thr 20 25 30 Thr Ser Ala Asn Glu Asn SerThr Val Leu Pro Ser Ser Thr Ser 35 40 45 Ser Ser Ser Asp Gly Asn Leu ArgPro Glu Ala Ile Thr Ala Ile 50 55 60 Ile Val Val Phe Ser Leu Leu Ala AlaLeu Leu Leu Ala Val Gly 65 70 75 Leu Ala Leu Leu Val Arg Lys Leu Arg GluLys Arg Gln Thr Glu 80 85 90 Gly Thr Tyr Arg Pro Ser Ser Glu Glu Gln PheSer His Ala Ala 95 100 105 Glu Ala Arg Ala Pro Gln Asp Ser Lys Glu ThrVal Gln Gly Cys 110 115 120 Leu Pro Ile 69 3265 DNA Homo Sapien 69gccaggaata actagagagg aacaatgggg ttattcagag gttttgtttt 50 cctcttagttctgtgcctgc tgcaccagtc aaatacttcc ttcattaagc 100 tgaataataa tggctttgaagatattgtca ttgttataga tcctagtgtg 150 ccagaagatg aaaaaataat tgaacaaatagaggatatgg tgactacagc 200 ttctacgtac ctgtttgaag ccacagaaaa aagattttttttcaaaaatg 250 tatctatatt aattcctgag aattggaagg aaaatcctca gtacaaaagg300 ccaaaacatg aaaaccataa acatgctgat gttatagttg caccacctac 350actcccaggt agagatgaac catacaccaa gcagttcaca gaatgtggag 400 agaaaggcgaatacattcac ttcacccctg accttctact tggaaaaaaa 450 caaaatgaat atggaccaccaggcaaactg tttgtccatg agtgggctca 500 cctccggtgg ggagtgtttg atgagtacaatgaagatcag cctttctacc 550 gtgctaagtc aaaaaaaatc gaagcaacaa ggtgttccgcaggtatctct 600 ggtagaaata gagtttataa gtgtcaagga ggcagctgtc ttagtagagc650 atgcagaatt gattctacaa caaaactgta tggaaaagat tgtcaattct 700ttcctgataa agtacaaaca gaaaaagcat ccataatgtt tatgcaaagt 750 attgattctgttgttgaatt ttgtaacgaa aaaacccata atcaagaagc 800 tccaagccta caaaacataaagtgcaattt tagaagtaca tgggaggtga 850 ttagcaattc tgaggatttt aaaaacaccatacccatggt gacaccacct 900 cctccacctg tcttctcatt gctgaagatc agtcaaagaattgtgtgctt 950 agttcttgat aagtctggaa gcatgggggg taaggaccgc ctaaatcgaa1000 tgaatcaagc agcaaaacat ttcctgctgc agactgttga aaatggatcc 1050tgggtgggga tggttcactt tgatagtact gccactattg taaataagct 1100 aatccaaataaaaagcagtg atgaaagaaa cacactcatg gcaggattac 1150 ctacatatcc tctgggaggaacttccatct gctctggaat taaatatgca 1200 tttcaggtga ttggagagct acattcccaactcgatggat ccgaagtact 1250 gctgctgact gatggggagg ataacactgc aagttcttgtattgatgaag 1300 tgaaacaaag tggggccatt gttcatttta ttgctttggg aagagctgct1350 gatgaagcag taatagagat gagcaagata acaggaggaa gtcattttta 1400tgtttcagat gaagctcaga acaatggcct cattgatgct tttggggctc 1450 ttacatcaggaaatactgat ctctcccaga agtcccttca gctcgaaagt 1500 aagggattaa cactgaatagtaatgcctgg atgaacgaca ctgtcataat 1550 tgatagtaca gtgggaaagg acacgttctttctcatcaca tggaacagtc 1600 tgcctcccag tatttctctc tgggatccca gtggaacaataatggaaaat 1650 ttcacagtgg atgcaacttc caaaatggcc tatctcagta ttccaggaac1700 tgcaaaggtg ggcacttggg catacaatct tcaagccaaa gcgaacccag 1750aaacattaac tattacagta acttctcgag cagcaaattc ttctgtgcct 1800 ccaatcacagtgaatgctaa aatgaataag gacgtaaaca gtttccccag 1850 cccaatgatt gtttacgcagaaattctaca aggatatgta cctgttcttg 1900 gagccaatgt gactgctttc attgaatcacagaatggaca tacagaagtt 1950 ttggaacttt tggataatgg tgcaggcgct gattctttcaagaatgatgg 2000 agtctactcc aggtatttta cagcatatac agaaaatggc agatatagct2050 taaaagttcg ggctcatgga ggagcaaaca ctgccaggct aaaattacgg 2100cctccactga atagagccgc gtacatacca ggctgggtag tgaacgggga 2150 aattgaagcaaacccgccaa gacctgaaat tgatgaggat actcagacca 2200 ccttggagga tttcagccgaacagcatccg gaggtgcatt tgtggtatca 2250 caagtcccaa gccttccctt gcctgaccaatacccaccaa gtcaaatcac 2300 agaccttgat gccacagttc atgaggataa gattattcttacatggacag 2350 caccaggaga taattttgat gttggaaaag ttcaacgtta tatcataaga2400 ataagtgcaa gtattcttga tctaagagac agttttgatg atgctcttca 2450agtaaatact actgatctgt caccaaagga ggccaactcc aaggaaagct 2500 ttgcatttaaaccagaaaat atctcagaag aaaatgcaac ccacatattt 2550 attgccatta aaagtatagataaaagcaat ttgacatcaa aagtatccaa 2600 cattgcacaa gtaactttgt ttatccctcaagcaaatcct gatgacattg 2650 atcctacacc tactcctact cctactccta ctcctgataaaagtcataat 2700 tctggagtta atatttctac gctggtattg tctgtgattg ggtctgttgt2750 aattgttaac tttattttaa gtaccaccat ttgaacctta acgaagaaaa 2800aaatcttcaa gtagacctag aagagagttt taaaaaacaa aacaatgtaa 2850 gtaaaggatatttctgaatc ttaaaattca tcccatgtgt gatcataaac 2900 tcataaaaat aattttaagatgtcggaaaa ggatactttg attaaataaa 2950 aacactcatg gatatgtaaa aactgtcaagattaaaattt aatagtttca 3000 tttatttgtt attttatttg taagaaatag tgatgaacaaagatcctttt 3050 tcatactgat acctggttgt atattatttg atgcaacagt tttctgaaat3100 gatatttcaa attgcatcaa gaaattaaaa tcatctatct gagtagtcaa 3150aatacaagta aaggagagca aataaacaac atttggaaaa aaaaaaaaaa 3200 aaaaaaaaaaaaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 3250 aaaaaaaaaa aaaaa 326570 919 PRT Homo Sapien 70 Met Gly Leu Phe Arg Gly Phe Val Phe Leu LeuVal Leu Cys Leu 1 5 10 15 Leu His Gln Ser Asn Thr Ser Phe Ile Lys LeuAsn Asn Asn Gly 20 25 30 Phe Glu Asp Ile Val Ile Val Ile Asp Pro Ser ValPro Glu Asp 35 40 45 Glu Lys Ile Ile Glu Gln Ile Glu Asp Met Val Thr ThrAla Ser 50 55 60 Thr Tyr Leu Phe Glu Ala Thr Glu Lys Arg Phe Phe Phe LysAsn 65 70 75 Val Ser Ile Leu Ile Pro Glu Asn Trp Lys Glu Asn Pro Gln Tyr80 85 90 Lys Arg Pro Lys His Glu Asn His Lys His Ala Asp Val Ile Val 95100 105 Ala Pro Pro Thr Leu Pro Gly Arg Asp Glu Pro Tyr Thr Lys Gln 110115 120 Phe Thr Glu Cys Gly Glu Lys Gly Glu Tyr Ile His Phe Thr Pro 125130 135 Asp Leu Leu Leu Gly Lys Lys Gln Asn Glu Tyr Gly Pro Pro Gly 140145 150 Lys Leu Phe Val His Glu Trp Ala His Leu Arg Trp Gly Val Phe 155160 165 Asp Glu Tyr Asn Glu Asp Gln Pro Phe Tyr Arg Ala Lys Ser Lys 170175 180 Lys Ile Glu Ala Thr Arg Cys Ser Ala Gly Ile Ser Gly Arg Asn 185190 195 Arg Val Tyr Lys Cys Gln Gly Gly Ser Cys Leu Ser Arg Ala Cys 200205 210 Arg Ile Asp Ser Thr Thr Lys Leu Tyr Gly Lys Asp Cys Gln Phe 215220 225 Phe Pro Asp Lys Val Gln Thr Glu Lys Ala Ser Ile Met Phe Met 230235 240 Gln Ser Ile Asp Ser Val Val Glu Phe Cys Asn Glu Lys Thr His 245250 255 Asn Gln Glu Ala Pro Ser Leu Gln Asn Ile Lys Cys Asn Phe Arg 260265 270 Ser Thr Trp Glu Val Ile Ser Asn Ser Glu Asp Phe Lys Asn Thr 275280 285 Ile Pro Met Val Thr Pro Pro Pro Pro Pro Val Phe Ser Leu Leu 290295 300 Lys Ile Ser Gln Arg Ile Val Cys Leu Val Leu Asp Lys Ser Gly 305310 315 Ser Met Gly Gly Lys Asp Arg Leu Asn Arg Met Asn Gln Ala Ala 320325 330 Lys His Phe Leu Leu Gln Thr Val Glu Asn Gly Ser Trp Val Gly 335340 345 Met Val His Phe Asp Ser Thr Ala Thr Ile Val Asn Lys Leu Ile 350355 360 Gln Ile Lys Ser Ser Asp Glu Arg Asn Thr Leu Met Ala Gly Leu 365370 375 Pro Thr Tyr Pro Leu Gly Gly Thr Ser Ile Cys Ser Gly Ile Lys 380385 390 Tyr Ala Phe Gln Val Ile Gly Glu Leu His Ser Gln Leu Asp Gly 395400 405 Ser Glu Val Leu Leu Leu Thr Asp Gly Glu Asp Asn Thr Ala Ser 410415 420 Ser Cys Ile Asp Glu Val Lys Gln Ser Gly Ala Ile Val His Phe 425430 435 Ile Ala Leu Gly Arg Ala Ala Asp Glu Ala Val Ile Glu Met Ser 440445 450 Lys Ile Thr Gly Gly Ser His Phe Tyr Val Ser Asp Glu Ala Gln 455460 465 Asn Asn Gly Leu Ile Asp Ala Phe Gly Ala Leu Thr Ser Gly Asn 470475 480 Thr Asp Leu Ser Gln Lys Ser Leu Gln Leu Glu Ser Lys Gly Leu 485490 495 Thr Leu Asn Ser Asn Ala Trp Met Asn Asp Thr Val Ile Ile Asp 500505 510 Ser Thr Val Gly Lys Asp Thr Phe Phe Leu Ile Thr Trp Asn Ser 515520 525 Leu Pro Pro Ser Ile Ser Leu Trp Asp Pro Ser Gly Thr Ile Met 530535 540 Glu Asn Phe Thr Val Asp Ala Thr Ser Lys Met Ala Tyr Leu Ser 545550 555 Ile Pro Gly Thr Ala Lys Val Gly Thr Trp Ala Tyr Asn Leu Gln 560565 570 Ala Lys Ala Asn Pro Glu Thr Leu Thr Ile Thr Val Thr Ser Arg 575580 585 Ala Ala Asn Ser Ser Val Pro Pro Ile Thr Val Asn Ala Lys Met 590595 600 Asn Lys Asp Val Asn Ser Phe Pro Ser Pro Met Ile Val Tyr Ala 605610 615 Glu Ile Leu Gln Gly Tyr Val Pro Val Leu Gly Ala Asn Val Thr 620625 630 Ala Phe Ile Glu Ser Gln Asn Gly His Thr Glu Val Leu Glu Leu 635640 645 Leu Asp Asn Gly Ala Gly Ala Asp Ser Phe Lys Asn Asp Gly Val 650655 660 Tyr Ser Arg Tyr Phe Thr Ala Tyr Thr Glu Asn Gly Arg Tyr Ser 665670 675 Leu Lys Val Arg Ala His Gly Gly Ala Asn Thr Ala Arg Leu Lys 680685 690 Leu Arg Pro Pro Leu Asn Arg Ala Ala Tyr Ile Pro Gly Trp Val 695700 705 Val Asn Gly Glu Ile Glu Ala Asn Pro Pro Arg Pro Glu Ile Asp 710715 720 Glu Asp Thr Gln Thr Thr Leu Glu Asp Phe Ser Arg Thr Ala Ser 725730 735 Gly Gly Ala Phe Val Val Ser Gln Val Pro Ser Leu Pro Leu Pro 740745 750 Asp Gln Tyr Pro Pro Ser Gln Ile Thr Asp Leu Asp Ala Thr Val 755760 765 His Glu Asp Lys Ile Ile Leu Thr Trp Thr Ala Pro Gly Asp Asn 770775 780 Phe Asp Val Gly Lys Val Gln Arg Tyr Ile Ile Arg Ile Ser Ala 785790 795 Ser Ile Leu Asp Leu Arg Asp Ser Phe Asp Asp Ala Leu Gln Val 800805 810 Asn Thr Thr Asp Leu Ser Pro Lys Glu Ala Asn Ser Lys Glu Ser 815820 825 Phe Ala Phe Lys Pro Glu Asn Ile Ser Glu Glu Asn Ala Thr His 830835 840 Ile Phe Ile Ala Ile Lys Ser Ile Asp Lys Ser Asn Leu Thr Ser 845850 855 Lys Val Ser Asn Ile Ala Gln Val Thr Leu Phe Ile Pro Gln Ala 860865 870 Asn Pro Asp Asp Ile Asp Pro Thr Pro Thr Pro Thr Pro Thr Pro 875880 885 Thr Pro Asp Lys Ser His Asn Ser Gly Val Asn Ile Ser Thr Leu 890895 900 Val Leu Ser Val Ile Gly Ser Val Val Ile Val Asn Phe Ile Leu 905910 915 Ser Thr Thr Ile 71 3877 DNA Homo Sapien 71 ctccttaggt ggaaaccctgggagtagagt actgacagca aagaccggga 50 aagaccatac gtccccgggc aggggtgacaacaggtgtca tctttttgat 100 ctcgtgtgtg gctgccttcc tatttcaagg aaagacgccaaggtaatttt 150 gacccagagg agcaatgatg tagccacctc ctaaccttcc cttcttgaac200 ccccagttat gccaggattt actagagagt gtcaactcaa ccagcaagcg 250gctccttcgg cttaacttgt ggttggagga gagaaccttt gtggggctgc 300 gttctcttagcagtgctcag aagtgacttg cctgagggtg gaccagaaga 350 aaggaaaggt cccctcttgctgttggctgc acatcaggaa ggctgtgatg 400 ggaatgaagg tgaaaacttg gagatttcacttcagtcatt gcttctgcct 450 gcaagatcat cctttaaaag tagagaagct gctctgtgtggtggttaact 500 ccaagaggca gaactcgttc tagaaggaaa tggatgcaag cagctccggg550 ggccccaaac gcatgcttcc tgtggtctag cccagggaag cccttccgtg 600ggggccccgg ctttgaggga tgccaccggt tctggacgca tggctgattc 650 ctgaatgatgatggttcgcc gggggctgct tgcgtggatt tcccgggtgg 700 tggttttgct ggtgctcctctgctgtgcta tctctgtcct gtacatgttg 750 gcctgcaccc caaaaggtga cgaggagcagctggcactgc ccagggccaa 800 cagccccacg gggaaggagg ggtaccaggc cgtccttcaggagtgggagg 850 agcagcaccg caactacgtg agcagcctga agcggcagat cgcacagctc900 aaggaggagc tgcaggagag gagtgagcag ctcaggaatg ggcagtacca 950agccagcgat gctgctggcc tgggtctgga caggagcccc ccagagaaaa 1000 cccaggccgacctcctggcc ttcctgcact cgcaggtgga caaggcagag 1050 gtgaatgctg gcgtcaagctggccacagag tatgcagcag tgcctttcga 1100 tagctttact ctacagaagg tgtaccagctggagactggc cttacccgcc 1150 accccgagga gaagcctgtg aggaaggaca agcgggatgagttggtggaa 1200 gccattgaat cagccttgga gaccctgaac aatcctgcag agaacagccc1250 caatcaccgt ccttacacgg cctctgattt catagaaggg atctaccgaa 1300cagaaaggga caaagggaca ttgtatgagc tcaccttcaa aggggaccac 1350 aaacacgaattcaaacggct catcttattt cgaccattca gccccatcat 1400 gaaagtgaaa aatgaaaagctcaacatggc caacacgctt atcaatgtta 1450 tcgtgcctct agcaaaaagg gtggacaagttccggcagtt catgcagaat 1500 ttcagggaga tgtgcattga gcaggatggg agagtccatctcactgttgt 1550 ttactttggg aaagaagaaa taaatgaagt caaaggaata cttgaaaaca1600 cttccaaagc tgccaacttc aggaacttta ccttcatcca gctgaatgga 1650gaattttctc ggggaaaggg acttgatgtt ggagcccgct tctggaaggg 1700 aagcaacgtccttctctttt tctgtgatgt ggacatctac ttcacatctg 1750 aattcctcaa tacgtgtaggctgaatacac agccagggaa gaaggtattt 1800 tatccagttc ttttcagtca gtacaatcctggcataatat acggccacca 1850 tgatgcagtc cctcccttgg aacagcagct ggtcataaagaaggaaactg 1900 gattttggag agactttgga tttgggatga cgtgtcagta tcggtcagac1950 ttcatcaata taggtgggtt tgatctggac atcaaaggct ggggcggaga 2000ggatgtgcac ctttatcgca agtatctcca cagcaacctc atagtggtac 2050 ggacgcctgtgcgaggactc ttccacctct ggcatgagaa gcgctgcatg 2100 gacgagctga cccccgagcagtacaagatg tgcatgcagt ccaaggccat 2150 gaacgaggca tcccacggcc agctgggcatgctggtgttc aggcacgaga 2200 tagaggctca ccttcgcaaa cagaaacaga agacaagtagcaaaaaaaca 2250 tgaactccca gagaaggatt gtgggagaca ctttttcttt ccttttgcaa2300 ttactgaaag tggctgcaac agagaaaaga cttccataaa ggacgacaaa 2350agaattggac tgatgggtca gagatgagaa agcctccgat ttctctctgt 2400 tgggctttttacaacagaaa tcaaaatctc cgctttgcct gcaaaagtaa 2450 cccagttgca ccctgtgaagtgtctgacaa aggcagaatg cttgtgagat 2500 tataagccta atggtgtgga ggttttgatggtgtttacaa tacactgaga 2550 cctgttgttt tgtgtgctca ttgaaatatt catgatttaagagcagtttt 2600 gtaaaaaatt cattagcatg aaaggcaagc atatttctcc tcatatgaat2650 gagcctatca gcagggctct agtttctagg aatgctaaaa tatcagaagg 2700caggagagga gataggctta ttatgatact agtgagtaca ttaagtaaaa 2750 taaaatggaccagaaaagaa aagaaaccat aaatatcgtg tcatattttc 2800 cccaagatta accaaaaataatctgcttat ctttttggtt gtccttttaa 2850 ctgtctccgt ttttttcttt tatttaaaaatgcacttttt ttcccttgtg 2900 agttatagtc tgcttattta attaccactt tgcaagccttacaagagagc 2950 acaagttggc ctacattttt atatttttta agaagatact ttgagatgca3000 ttatgagaac tttcagttca aagcatcaaa ttgatgccat atccaaggac 3050atgccaaatg ctgattctgt caggcactga atgtcaggca ttgagacata 3100 gggaaggaatggtttgtact aatacagacg tacagatact ttctctgaag 3150 agtattttcg aagaggagcaactgaacact ggaggaaaag aaaatgacac 3200 tttctgcttt acagaaaagg aaactcattcagactggtga tatcgtgatg 3250 tacctaaaag tcagaaacca cattttctcc tcagaagtagggaccgcttt 3300 cttacctgtt taaataaacc aaagtatacc gtgtgaacca aacaatctct3350 tttcaaaaca gggtgctcct cctggcttct ggcttccata agaagaaatg 3400gagaaaaata tatatatata tatatatatt gtgaaagatc aatccatctg 3450 ccagaatctagtgggatgga agtttttgct acatgttatc caccccaggc 3500 caggtggaag taactgaattattttttaaa ttaagcagtt ctactcaatc 3550 accaagatgc ttctgaaaat tgcattttattaccatttca aactattttt 3600 taaaaataaa tacagttaac atagagtggt ttcttcattcatgtgaaaat 3650 tattagccag caccagatgc atgagctaat tatctctttg agtccttgct3700 tctgtttgct cacagtaaac tcattgttta aaagcttcaa gaacattcaa 3750gctgttggtg tgttaaaaaa tgcattgtat tgatttgtac tggtagttta 3800 tgaaatttaattaaaacaca ggccatgaat ggaaggtggt attgcacagc 3850 taataaaata tgatttgtggatatgaa 3877 72 532 PRT Homo Sapien 72 Met Met Met Val Arg Arg Gly LeuLeu Ala Trp Ile Ser Arg Val 1 5 10 15 Val Val Leu Leu Val Leu Leu CysCys Ala Ile Ser Val Leu Tyr 20 25 30 Met Leu Ala Cys Thr Pro Lys Gly AspGlu Glu Gln Leu Ala Leu 35 40 45 Pro Arg Ala Asn Ser Pro Thr Gly Lys GluGly Tyr Gln Ala Val 50 55 60 Leu Gln Glu Trp Glu Glu Gln His Arg Asn TyrVal Ser Ser Leu 65 70 75 Lys Arg Gln Ile Ala Gln Leu Lys Glu Glu Leu GlnGlu Arg Ser 80 85 90 Glu Gln Leu Arg Asn Gly Gln Tyr Gln Ala Ser Asp AlaAla Gly 95 100 105 Leu Gly Leu Asp Arg Ser Pro Pro Glu Lys Thr Gln AlaAsp Leu 110 115 120 Leu Ala Phe Leu His Ser Gln Val Asp Lys Ala Glu ValAsn Ala 125 130 135 Gly Val Lys Leu Ala Thr Glu Tyr Ala Ala Val Pro PheAsp Ser 140 145 150 Phe Thr Leu Gln Lys Val Tyr Gln Leu Glu Thr Gly LeuThr Arg 155 160 165 His Pro Glu Glu Lys Pro Val Arg Lys Asp Lys Arg AspGlu Leu 170 175 180 Val Glu Ala Ile Glu Ser Ala Leu Glu Thr Leu Asn AsnPro Ala 185 190 195 Glu Asn Ser Pro Asn His Arg Pro Tyr Thr Ala Ser AspPhe Ile 200 205 210 Glu Gly Ile Tyr Arg Thr Glu Arg Asp Lys Gly Thr LeuTyr Glu 215 220 225 Leu Thr Phe Lys Gly Asp His Lys His Glu Phe Lys ArgLeu Ile 230 235 240 Leu Phe Arg Pro Phe Ser Pro Ile Met Lys Val Lys AsnGlu Lys 245 250 255 Leu Asn Met Ala Asn Thr Leu Ile Asn Val Ile Val ProLeu Ala 260 265 270 Lys Arg Val Asp Lys Phe Arg Gln Phe Met Gln Asn PheArg Glu 275 280 285 Met Cys Ile Glu Gln Asp Gly Arg Val His Leu Thr ValVal Tyr 290 295 300 Phe Gly Lys Glu Glu Ile Asn Glu Val Lys Gly Ile LeuGlu Asn 305 310 315 Thr Ser Lys Ala Ala Asn Phe Arg Asn Phe Thr Phe IleGln Leu 320 325 330 Asn Gly Glu Phe Ser Arg Gly Lys Gly Leu Asp Val GlyAla Arg 335 340 345 Phe Trp Lys Gly Ser Asn Val Leu Leu Phe Phe Cys AspVal Asp 350 355 360 Ile Tyr Phe Thr Ser Glu Phe Leu Asn Thr Cys Arg LeuAsn Thr 365 370 375 Gln Pro Gly Lys Lys Val Phe Tyr Pro Val Leu Phe SerGln Tyr 380 385 390 Asn Pro Gly Ile Ile Tyr Gly His His Asp Ala Val ProPro Leu 395 400 405 Glu Gln Gln Leu Val Ile Lys Lys Glu Thr Gly Phe TrpArg Asp 410 415 420 Phe Gly Phe Gly Met Thr Cys Gln Tyr Arg Ser Asp PheIle Asn 425 430 435 Ile Gly Gly Phe Asp Leu Asp Ile Lys Gly Trp Gly GlyGlu Asp 440 445 450 Val His Leu Tyr Arg Lys Tyr Leu His Ser Asn Leu IleVal Val 455 460 465 Arg Thr Pro Val Arg Gly Leu Phe His Leu Trp His GluLys Arg 470 475 480 Cys Met Asp Glu Leu Thr Pro Glu Gln Tyr Lys Met CysMet Gln 485 490 495 Ser Lys Ala Met Asn Glu Ala Ser His Gly Gln Leu GlyMet Leu 500 505 510 Val Phe Arg His Glu Ile Glu Ala His Leu Arg Lys GlnLys Gln 515 520 525 Lys Thr Ser Ser Lys Lys Thr 530 73 1701 DNA HomoSapien unsure 1528 unknown base 73 gagactgcag agggagataa agagagagggcaaagaggca gcaagagatt 50 tgtcctgggg atccagaaac ccatgatacc ctactgaacaccgaatcccc 100 tggaagccca cagagacaga gacagcaaga gaagcagaga taaatacact150 cacgccagga gctcgctcgc tctctctctc tctctctcac tcctccctcc 200ctctctctct gcctgtccta gtcctctagt cctcaaattc ccagtcccct 250 gcaccccttcctgggacact atgttgttct ccgccctcct gctggaggtg 300 atttggatcc tggctgcagatgggggtcaa cactggacgt atgagggccc 350 acatggtcag gaccattggc cagcctcttaccctgagtgt ggaaacaatg 400 cccagtcgcc catcgatatt cagacagaca gtgtgacatttgaccctgat 450 ttgcctgctc tgcagcccca cggatatgac cagcctggca ccgagccttt500 ggacctgcac aacaatggcc acacagtgca actctctctg ccctctaccc 550tgtatctggg tggacttccc cgaaaatatg tagctgccca gctccacctg 600 cactggggtcagaaaggatc cccagggggg tcagaacacc agatcaacag 650 tgaagccaca tttgcagagctccacattgt acattatgac tctgattcct 700 atgacagctt gagtgaggct gctgagaggcctcagggcct ggctgtcctg 750 ggcatcctaa ttgaggtggg tgagactaag aatatagcttatgaacacat 800 tctgagtcac ttgcatgaag tcaggcataa agatcagaag acctcagtgc850 ctcccttcaa cctaagagag ctgctcccca aacagctggg gcagtacttc 900cgctacaatg gctcgctcac aactccccct tgctaccaga gtgtgctctg 950 gacagttttttatagaaggt cccagatttc aatggaacag ctggaaaagc 1000 ttcaggggac attgttctccacagaagagg agccctctaa gcttctggta 1050 cagaactacc gagcccttca gcctctcaatcagcgcatgg tctttgcttc 1100 tttcatccaa gcaggatcct cgtataccac aggtgaaatgctgagtctag 1150 gtgtaggaat cttggttggc tgtctctgcc ttctcctggc tgtttatttc1200 attgctagaa agattcggaa gaagaggctg gaaaaccgaa agagtgtggt 1250cttcacctca gcacaagcca cgactgaggc ataaattcct tctcagatac 1300 catggatgtggatgacttcc cttcatgcct atcaggaagc ctctaaaatg 1350 gggtgtagga tctggccagaaacactgtag gagtagtaag cagatgtcct 1400 ccttcccctg gacatctctt agagaggaatggacccaggc tgtcattcca 1450 ggaagaactg cagagccttc agcctctcca aacatgtaggaggaaatgag 1500 gaaatcgctg tgttgttaat gcagaganca aactctgttt agttgcaggg1550 gaagtttggg atatacccca aagtcctcta ccccctcact tttatggccc 1600tttccctaga tatactgcgg gatctctcct taggataaag agttgctgtt 1650 gaagttgtatatttttgatc aatatatttg gaaattaaag tttctgactt 1700 t 1701 74 337 PRT HomoSapien 74 Met Leu Phe Ser Ala Leu Leu Leu Glu Val Ile Trp Ile Leu Ala 15 10 15 Ala Asp Gly Gly Gln His Trp Thr Tyr Glu Gly Pro His Gly Gln 2025 30 Asp His Trp Pro Ala Ser Tyr Pro Glu Cys Gly Asn Asn Ala Gln 35 4045 Ser Pro Ile Asp Ile Gln Thr Asp Ser Val Thr Phe Asp Pro Asp 50 55 60Leu Pro Ala Leu Gln Pro His Gly Tyr Asp Gln Pro Gly Thr Glu 65 70 75 ProLeu Asp Leu His Asn Asn Gly His Thr Val Gln Leu Ser Leu 80 85 90 Pro SerThr Leu Tyr Leu Gly Gly Leu Pro Arg Lys Tyr Val Ala 95 100 105 Ala GlnLeu His Leu His Trp Gly Gln Lys Gly Ser Pro Gly Gly 110 115 120 Ser GluHis Gln Ile Asn Ser Glu Ala Thr Phe Ala Glu Leu His 125 130 135 Ile ValHis Tyr Asp Ser Asp Ser Tyr Asp Ser Leu Ser Glu Ala 140 145 150 Ala GluArg Pro Gln Gly Leu Ala Val Leu Gly Ile Leu Ile Glu 155 160 165 Val GlyGlu Thr Lys Asn Ile Ala Tyr Glu His Ile Leu Ser His 170 175 180 Leu HisGlu Val Arg His Lys Asp Gln Lys Thr Ser Val Pro Pro 185 190 195 Phe AsnLeu Arg Glu Leu Leu Pro Lys Gln Leu Gly Gln Tyr Phe 200 205 210 Arg TyrAsn Gly Ser Leu Thr Thr Pro Pro Cys Tyr Gln Ser Val 215 220 225 Leu TrpThr Val Phe Tyr Arg Arg Ser Gln Ile Ser Met Glu Gln 230 235 240 Leu GluLys Leu Gln Gly Thr Leu Phe Ser Thr Glu Glu Glu Pro 245 250 255 Ser LysLeu Leu Val Gln Asn Tyr Arg Ala Leu Gln Pro Leu Asn 260 265 270 Gln ArgMet Val Phe Ala Ser Phe Ile Gln Ala Gly Ser Ser Tyr 275 280 285 Thr ThrGly Glu Met Leu Ser Leu Gly Val Gly Ile Leu Val Gly 290 295 300 Cys LeuCys Leu Leu Leu Ala Val Tyr Phe Ile Ala Arg Lys Ile 305 310 315 Arg LysLys Arg Leu Glu Asn Arg Lys Ser Val Val Phe Thr Ser 320 325 330 Ala GlnAla Thr Thr Glu Ala 335 75 1743 DNA Homo Sapien 75 tgccgctgcc gccgctgctgctgttgctcc tggcggcgcc ttggggacgg 50 gcagttccct gtgtctctgg tggtttgcctaaacctgcaa acatcacctt 100 cttatccatc aacatgaaga atgtcctaca atggactccaccagagggtc 150 ttcaaggagt taaagttact tacactgtgc agtatttcat cacaaattgg200 cccaccagag gtggcactga ctacagatga gaagtccatt tctgttgtcc 250tgacagctcc agagaagtgg aagagaaatc cagaagacct tcctgtttcc 300 atgcaacaaatatactccaa tctgaagtat aacgtgtctg tgttgaatac 350 taaatcaaac agaacgtggtcccagtgtgt gaccaaccac acgctggtgc 400 tcacctggct ggagccgaac actctttactgcgtacacgt ggagtccttc 450 gtcccagggc cccctcgccg tgctcagcct tctgagaagcagtgtgccag 500 gactttgaaa gatcaatcat cagagttcaa ggctaaaatc atcttctggt550 atgttttgcc catatctatt accgtgtttc ttttttctgt gatgggctat 600tccatctacc gatatatcca cgttggcaaa gagaaacacc cagcaaattt 650 gattttgatttatggaaatg aatttgacaa aagattcttt gtgcctgctg 700 aaaaaatcgt gattaactttatcaccctca atatctcgga tgattctaaa 750 atttctcatc aggatatgag tttactgggaaaaagcagtg atgtatccag 800 ccttaatgat cctcagccca gcgggaacct gaggccccctcaggaggaag 850 aggaggtgaa acatttaggg tatgcttcgc atttgatgga aattttttgt900 gactctgaag aaaacacgga aggtacttct ctcacccagc aagagtccct 950cagcagaaca atacccccgg ataaaacagt cattgaatat gaatatgatg 1000 tcagaaccactgacatttgt gcggggcctg aagagcagga gctcagtttg 1050 caggaggagg tgtccacacaaggaacatta ttggagtcgc aggcagcgtt 1100 ggcagtcttg ggcccgcaaa cgttacagtactcatacacc cctcagctcc 1150 aagacttaga ccccctggcg caggagcaca cagactcggaggaggggccg 1200 gaggaagagc catcgacgac cctggtcgac tgggatcccc aaactggcag1250 gctgtgtatt ccttcgctgt ccagcttcga ccaggattca gagggctgcg 1300agccttctga gggggatggg ctcggagagg agggtcttct atctagactc 1350 tatgaggagccggctccaga caggccacca ggagaaaatg aaacctatct 1400 catgcaattc atggaggaatgggggttata tgtgcagatg gaaaactgat 1450 gccaacactt ccttttgcct tttgtttcctgtgcaaacaa gtgagtcacc 1500 cctttgatcc cagccataaa gtacctggga tgaaagaagttttttccagt 1550 ttgtcagtgt ctgtgagaat tacttatttc ttttctctat tctcatagca1600 cgtgtgtgat tggttcatgc atgtaggtct cttaacaatg atggtgggcc 1650tctggagtcc aggggctggc cggttgttct atgcagagaa agcagtcaat 1700 aaatgtttgccagactgggt gcagaattta ttcaggtggg tgt 1743 76 442 PRT Homo Sapien 76 MetSer Tyr Asn Gly Leu His Gln Arg Val Phe Lys Glu Leu Lys 1 5 10 15 LeuLeu Thr Leu Cys Ser Ile Ser Ser Gln Ile Gly Pro Pro Glu 20 25 30 Val AlaLeu Thr Thr Asp Glu Lys Ser Ile Ser Val Val Leu Thr 35 40 45 Ala Pro GluLys Trp Lys Arg Asn Pro Glu Asp Leu Pro Val Ser 50 55 60 Met Gln Gln IleTyr Ser Asn Leu Lys Tyr Asn Val Ser Val Leu 65 70 75 Asn Thr Lys Ser AsnArg Thr Trp Ser Gln Cys Val Thr Asn His 80 85 90 Thr Leu Val Leu Thr TrpLeu Glu Pro Asn Thr Leu Tyr Cys Val 95 100 105 His Val Glu Ser Phe ValPro Gly Pro Pro Arg Arg Ala Gln Pro 110 115 120 Ser Glu Lys Gln Cys AlaArg Thr Leu Lys Asp Gln Ser Ser Glu 125 130 135 Phe Lys Ala Lys Ile IlePhe Trp Tyr Val Leu Pro Ile Ser Ile 140 145 150 Thr Val Phe Leu Phe SerVal Met Gly Tyr Ser Ile Tyr Arg Tyr 155 160 165 Ile His Val Gly Lys GluLys His Pro Ala Asn Leu Ile Leu Ile 170 175 180 Tyr Gly Asn Glu Phe AspLys Arg Phe Phe Val Pro Ala Glu Lys 185 190 195 Ile Val Ile Asn Phe IleThr Leu Asn Ile Ser Asp Asp Ser Lys 200 205 210 Ile Ser His Gln Asp MetSer Leu Leu Gly Lys Ser Ser Asp Val 215 220 225 Ser Ser Leu Asn Asp ProGln Pro Ser Gly Asn Leu Arg Pro Pro 230 235 240 Gln Glu Glu Glu Glu ValLys His Leu Gly Tyr Ala Ser His Leu 245 250 255 Met Glu Ile Phe Cys AspSer Glu Glu Asn Thr Glu Gly Thr Ser 260 265 270 Leu Thr Gln Gln Glu SerLeu Ser Arg Thr Ile Pro Pro Asp Lys 275 280 285 Thr Val Ile Glu Tyr GluTyr Asp Val Arg Thr Thr Asp Ile Cys 290 295 300 Ala Gly Pro Glu Glu GlnGlu Leu Ser Leu Gln Glu Glu Val Ser 305 310 315 Thr Gln Gly Thr Leu LeuGlu Ser Gln Ala Ala Leu Ala Val Leu 320 325 330 Gly Pro Gln Thr Leu GlnTyr Ser Tyr Thr Pro Gln Leu Gln Asp 335 340 345 Leu Asp Pro Leu Ala GlnGlu His Thr Asp Ser Glu Glu Gly Pro 350 355 360 Glu Glu Glu Pro Ser ThrThr Leu Val Asp Trp Asp Pro Gln Thr 365 370 375 Gly Arg Leu Cys Ile ProSer Leu Ser Ser Phe Asp Gln Asp Ser 380 385 390 Glu Gly Cys Glu Pro SerGlu Gly Asp Gly Leu Gly Glu Glu Gly 395 400 405 Leu Leu Ser Arg Leu TyrGlu Glu Pro Ala Pro Asp Arg Pro Pro 410 415 420 Gly Glu Asn Glu Thr TyrLeu Met Gln Phe Met Glu Glu Trp Gly 425 430 435 Leu Tyr Val Gln Met GluAsn 440 77 1636 DNA Homo Sapien 77 gaggagcggg ccgaggactc cagcgtgcccaggtctggca tcctgcactt 50 gctgccctct gacacctggg aagatggccg gcccgtggaccttcaccctt 100 ctctgtggtt tgctggcagc caccttgatc caagccaccc tcagtcccac150 tgcagttctc atcctcggcc caaaagtcat caaagaaaag ctgacacagg 200agctgaagga ccacaacgcc accagcatcc tgcagcagct gccgctgctc 250 agtgccatgcgggaaaagcc agccggaggc atccctgtgc tgggcagcct 300 ggtgaacacc gtcctgaagcacatcatctg gctgaaggtc atcacagcta 350 acatcctcca gctgcaggtg aagccctcggccaatgacca ggagctgcta 400 gtcaagatcc ccctggacat ggtggctgga ttcaacacgcccctggtcaa 450 gaccatcgtg gagttccaca tgacgactga ggcccaagcc accatccgca500 tggacaccag tgcaagtggc cccacccgcc tggtcctcag tgactgtgcc 550accagccatg ggagcctgcg catccaactg ctgtataagc tctccttcct 600 ggtgaacgccttagctaagc aggtcatgaa cctcctagtg ccatccctgc 650 ccaatctagt gaaaaaccagctgtgtcccg tgatcgaggc ttccttcaat 700 ggcatgtatg cagacctcct gcagctggtgaaggtgccca tttccctcag 750 cattgaccgt ctggagtttg accttctgta tcctgccatcaagggtgaca 800 ccattcagct ctacctgggg gccaagttgt tggactcaca gggaaaggtg850 accaagtggt tcaataactc tgcagcttcc ctgacaatgc ccaccctgga 900caacatcccg ttcagcctca tcgtgagtca ggacgtggtg aaagctgcag 950 tggctgctgtgctctctcca gaagaattca tggtcctgtt ggactctgtg 1000 cttcctgaga gtgcccatcggctgaagtca agcatcgggc tgatcaatga 1050 aaaggctgca gataagctgg gatctacccagatcgtgaag atcctaactc 1100 aggacactcc cgagtttttt atagaccaag gccatgccaaggtggcccaa 1150 ctgatcgtgc tggaagtgtt tccctccagt gaagccctcc gccctttgtt1200 caccctgggc atcgaagcca gctcggaagc tcagttttac accaaaggtg 1250accaacttat actcaacttg aataacatca gctctgatcg gatccagctg 1300 atgaactctgggattggctg gttccaacct gatgttctga aaaacatcat 1350 cactgagatc atccactccatcctgctgcc gaaccagaat ggcaaattaa 1400 gatctggggt cccagtgtca ttggtgaaggccttgggatt cgaggcagct 1450 gagtcctcac tgaccaagga tgcccttgtg cttactccagcctccttgtg 1500 gaaacccagc tctcctgtct cccagtgaag acttggatgg cagccatcag1550 ggaaggctgg gtcccagctg ggagtatggg tgtgagctct atagaccatc 1600cctctctgca atcaataaac acttgcctgt gaaaaa 1636 78 484 PRT Homo Sapien 78Met Ala Gly Pro Trp Thr Phe Thr Leu Leu Cys Gly Leu Leu Ala 1 5 10 15Ala Thr Leu Ile Gln Ala Thr Leu Ser Pro Thr Ala Val Leu Ile 20 25 30 LeuGly Pro Lys Val Ile Lys Glu Lys Leu Thr Gln Glu Leu Lys 35 40 45 Asp HisAsn Ala Thr Ser Ile Leu Gln Gln Leu Pro Leu Leu Ser 50 55 60 Ala Met ArgGlu Lys Pro Ala Gly Gly Ile Pro Val Leu Gly Ser 65 70 75 Leu Val Asn ThrVal Leu Lys His Ile Ile Trp Leu Lys Val Ile 80 85 90 Thr Ala Asn Ile LeuGln Leu Gln Val Lys Pro Ser Ala Asn Asp 95 100 105 Gln Glu Leu Leu ValLys Ile Pro Leu Asp Met Val Ala Gly Phe 110 115 120 Asn Thr Pro Leu ValLys Thr Ile Val Glu Phe His Met Thr Thr 125 130 135 Glu Ala Gln Ala ThrIle Arg Met Asp Thr Ser Ala Ser Gly Pro 140 145 150 Thr Arg Leu Val LeuSer Asp Cys Ala Thr Ser His Gly Ser Leu 155 160 165 Arg Ile Gln Leu LeuTyr Lys Leu Ser Phe Leu Val Asn Ala Leu 170 175 180 Ala Lys Gln Val MetAsn Leu Leu Val Pro Ser Leu Pro Asn Leu 185 190 195 Val Lys Asn Gln LeuCys Pro Val Ile Glu Ala Ser Phe Asn Gly 200 205 210 Met Tyr Ala Asp LeuLeu Gln Leu Val Lys Val Pro Ile Ser Leu 215 220 225 Ser Ile Asp Arg LeuGlu Phe Asp Leu Leu Tyr Pro Ala Ile Lys 230 235 240 Gly Asp Thr Ile GlnLeu Tyr Leu Gly Ala Lys Leu Leu Asp Ser 245 250 255 Gln Gly Lys Val ThrLys Trp Phe Asn Asn Ser Ala Ala Ser Leu 260 265 270 Thr Met Pro Thr LeuAsp Asn Ile Pro Phe Ser Leu Ile Val Ser 275 280 285 Gln Asp Val Val LysAla Ala Val Ala Ala Val Leu Ser Pro Glu 290 295 300 Glu Phe Met Val LeuLeu Asp Ser Val Leu Pro Glu Ser Ala His 305 310 315 Arg Leu Lys Ser SerIle Gly Leu Ile Asn Glu Lys Ala Ala Asp 320 325 330 Lys Leu Gly Ser ThrGln Ile Val Lys Ile Leu Thr Gln Asp Thr 335 340 345 Pro Glu Phe Phe IleAsp Gln Gly His Ala Lys Val Ala Gln Leu 350 355 360 Ile Val Leu Glu ValPhe Pro Ser Ser Glu Ala Leu Arg Pro Leu 365 370 375 Phe Thr Leu Gly IleGlu Ala Ser Ser Glu Ala Gln Phe Tyr Thr 380 385 390 Lys Gly Asp Gln LeuIle Leu Asn Leu Asn Asn Ile Ser Ser Asp 395 400 405 Arg Ile Gln Leu MetAsn Ser Gly Ile Gly Trp Phe Gln Pro Asp 410 415 420 Val Leu Lys Asn IleIle Thr Glu Ile Ile His Ser Ile Leu Leu 425 430 435 Pro Asn Gln Asn GlyLys Leu Arg Ser Gly Val Pro Val Ser Leu 440 445 450 Val Lys Ala Leu GlyPhe Glu Ala Ala Glu Ser Ser Leu Thr Lys 455 460 465 Asp Ala Leu Val LeuThr Pro Ala Ser Leu Trp Lys Pro Ser Ser 470 475 480 Pro Val Ser Gln 791475 DNA Homo Sapien 79 gagagaagtc agcctggcag agagactctg aaatgagggattagaggtgt 50 tcaaggagca agagcttcag cctgaagaca agggagcagt ccctgaagac 100gcttctactg agaggtctgc catggcctct cttggcctcc aacttgtggg 150 ctacatcctaggccttctgg ggcttttggg cacactggtt gccatgctgc 200 tccccagctg gaaaacaagttcttatgtcg gtgccagcat tgtgacagca 250 gttggcttct ccaagggcct ctggatggaatgtgccacac acagcacagg 300 catcacccag tgtgacatct atagcaccct tctgggcctgcccgctgaca 350 tccaggctgc ccaggccatg atggtgacat ccagtgcaat ctcctccctg400 gcctgcatta tctctgtggt gggcatgaga tgcacagtct tctgccagga 450atcccgagcc aaagacagag tggcggtagc aggtggagtc tttttcatcc 500 ttggaggcctcctgggattc attcctgttg cctggaatct tcatgggatc 550 ctacgggact tctactcaccactggtgcct gacagcatga aatttgagat 600 tggagaggct ctttacttgg gcattatttcttccctgttc tccctgatag 650 ctggaatcat cctctgcttt tcctgctcat cccagagaaatcgctccaac 700 tactacgatg cctaccaagc ccaacctctt gccacaagga gctctccaag750 gcctggtcaa cctcccaaag tcaagagtga gttcaattcc tacagcctga 800cagggtatgt gtgaagaacc aggggccaga gctggggggt ggctgggtct 850 gtgaaaaacagtggacagca ccccgagggc cacaggtgag ggacactacc 900 actggatcgt gtcagaaggtgctgctgagg atagactgac tttggccatt 950 ggattgagca aaggcagaaa tgggggctagtgtaacagca tgcaggttga 1000 attgccaagg atgctcgcca tgccagcctt tctgttttcctcaccttgct 1050 gctcccctgc cctaagtccc caaccctcaa cttgaaaccc cattccctta1100 agccaggact cagaggatcc ctttgccctc tggtttacct gggactccat 1150ccccaaaccc actaatcaca tcccactgac tgaccctctg tgatcaaaga 1200 ccctctctctggctgaggtt ggctcttagc tcattgctgg ggatgggaag 1250 gagaagcagt ggcttttgtgggcattgctc taacctactt ctcaagcttc 1300 cctccaaaga aactgattgg ccctggaacctccatcccac tcttgttatg 1350 actccacagt gtccagacta atttgtgcat gaactgaaataaaaccatcc 1400 tacggtatcc agggaacaga aagcaggatg caggatggga ggacaggaag1450 gcagcctggg acatttaaaa aaata 1475 80 230 PRT Homo Sapien 80 Met AlaSer Leu Gly Leu Gln Leu Val Gly Tyr Ile Leu Gly Leu 1 5 10 15 Leu GlyLeu Leu Gly Thr Leu Val Ala Met Leu Leu Pro Ser Trp 20 25 30 Lys Thr SerSer Tyr Val Gly Ala Ser Ile Val Thr Ala Val Gly 35 40 45 Phe Ser Lys GlyLeu Trp Met Glu Cys Ala Thr His Ser Thr Gly 50 55 60 Ile Thr Gln Cys AspIle Tyr Ser Thr Leu Leu Gly Leu Pro Ala 65 70 75 Asp Ile Gln Ala Ala GlnAla Met Met Val Thr Ser Ser Ala Ile 80 85 90 Ser Ser Leu Ala Cys Ile IleSer Val Val Gly Met Arg Cys Thr 95 100 105 Val Phe Cys Gln Glu Ser ArgAla Lys Asp Arg Val Ala Val Ala 110 115 120 Gly Gly Val Phe Phe Ile LeuGly Gly Leu Leu Gly Phe Ile Pro 125 130 135 Val Ala Trp Asn Leu His GlyIle Leu Arg Asp Phe Tyr Ser Pro 140 145 150 Leu Val Pro Asp Ser Met LysPhe Glu Ile Gly Glu Ala Leu Tyr 155 160 165 Leu Gly Ile Ile Ser Ser LeuPhe Ser Leu Ile Ala Gly Ile Ile 170 175 180 Leu Cys Phe Ser Cys Ser SerGln Arg Asn Arg Ser Asn Tyr Tyr 185 190 195 Asp Ala Tyr Gln Ala Gln ProLeu Ala Thr Arg Ser Ser Pro Arg 200 205 210 Pro Gly Gln Pro Pro Lys ValLys Ser Glu Phe Asn Ser Tyr Ser 215 220 225 Leu Thr Gly Tyr Val 230 811732 DNA Homo Sapien 81 cccacgcgtc cgcgcctctc ccttctgctg gaccttccttcgtctctcca 50 tctctccctc ctttccccgc gttctctttc cacctttctc ttcttcccac 100cttagacctc ccttcctgcc ctcctttcct gcccaccgct gcttcctggc 150 ccttctccgaccccgctcta gcagcagacc tcctggggtc tgtgggttga 200 tctgtggccc ctgtgcctccgtgtcctttt cgtctccctt cctcccgact 250 ccgctcccgg accagcggcc tgaccctggggaaaggatgg ttcccgaggt 300 gagggtcctc tcctccttgc tgggactcgc gctgctctggttccccctgg 350 actcccacgc tcgagcccgc ccagacatgt tctgcctttt ccatgggaag400 agatactccc ccggcgagag ctggcacccc tacttggagc cacaaggcct 450gatgtactgc ctgcgctgta cctgctcaga gggcgcccat gtgagttgtt 500 accgcctccactgtccgcct gtccactgcc cccagcctgt gacggagcca 550 cagcaatgct gtcccaagtgtgtggaacct cacactccct ctggactccg 600 ggccccacca aagtcctgcc agcacaacgggaccatgtac caacacggag 650 agatcttcag tgcccatgag ctgttcccct cccgcctgcccaaccagtgt 700 gtcctctgca gctgcacaga gggccagatc tactgcggcc tcacaacctg750 ccccgaacca ggctgcccag cacccctccc actgccagac tcctgctgcc 800aagcctgcaa agatgaggca agtgagcaat cggatgaaga ggacagtgtg 850 cagtcgctccatggggtgag acatcctcag gatccatgtt ccagtgatgc 900 tgggagaaag agaggcccgggcaccccagc ccccactggc ctcagcgccc 950 ctctgagctt catccctcgc cacttcagacccaagggagc aggcagcaca 1000 actgtcaaga tcgtcctgaa ggagaaacat aagaaagcctgtgtgcatgg 1050 cgggaagacg tactcccacg gggaggtgtg gcacccggcc ttccgtgcct1100 tcggcccctt gccctgcatc ctatgcacct gtgaggatgg ccgccaggac 1150tgccagcgtg tgacctgtcc caccgagtac ccctgccgtc accccgagaa 1200 agtggctgggaagtgctgca agatttgccc agaggacaaa gcagaccctg 1250 gccacagtga gatcagttctaccaggtgtc ccaaggcacc gggccgggtc 1300 ctcgtccaca catcggtatc cccaagcccagacaacctgc gtcgctttgc 1350 cctggaacac gaggcctcgg acttggtgga gatctacctctggaagctgg 1400 taaaagatga ggaaactgag gctcagagag gtgaagtacc tggcccaagg1450 ccacacagcc agaatcttcc acttgactca gatcaagaaa gtcaggaagc 1500aagacttcca gaaagaggca cagcacttcc gactgctcgc tggcccccac 1550 gaaggtcactggaacgtctt cctagcccag accctggagc tgaaggtcac 1600 ggccagtcca gacaaagtgaccaagacata acaaagacct aacagttgca 1650 gatatgagct gtataattgt tgttattatatattaataaa taagaagttg 1700 cattaccctc aaaaaaaaaa aaaaaaaaaa aa 1732 82451 PRT Homo Sapien 82 Met Val Pro Glu Val Arg Val Leu Ser Ser Leu LeuGly Leu Ala 1 5 10 15 Leu Leu Trp Phe Pro Leu Asp Ser His Ala Arg AlaArg Pro Asp 20 25 30 Met Phe Cys Leu Phe His Gly Lys Arg Tyr Ser Pro GlyGlu Ser 35 40 45 Trp His Pro Tyr Leu Glu Pro Gln Gly Leu Met Tyr Cys LeuArg 50 55 60 Cys Thr Cys Ser Glu Gly Ala His Val Ser Cys Tyr Arg Leu His65 70 75 Cys Pro Pro Val His Cys Pro Gln Pro Val Thr Glu Pro Gln Gln 8085 90 Cys Cys Pro Lys Cys Val Glu Pro His Thr Pro Ser Gly Leu Arg 95 100105 Ala Pro Pro Lys Ser Cys Gln His Asn Gly Thr Met Tyr Gln His 110 115120 Gly Glu Ile Phe Ser Ala His Glu Leu Phe Pro Ser Arg Leu Pro 125 130135 Asn Gln Cys Val Leu Cys Ser Cys Thr Glu Gly Gln Ile Tyr Cys 140 145150 Gly Leu Thr Thr Cys Pro Glu Pro Gly Cys Pro Ala Pro Leu Pro 155 160165 Leu Pro Asp Ser Cys Cys Gln Ala Cys Lys Asp Glu Ala Ser Glu 170 175180 Gln Ser Asp Glu Glu Asp Ser Val Gln Ser Leu His Gly Val Arg 185 190195 His Pro Gln Asp Pro Cys Ser Ser Asp Ala Gly Arg Lys Arg Gly 200 205210 Pro Gly Thr Pro Ala Pro Thr Gly Leu Ser Ala Pro Leu Ser Phe 215 220225 Ile Pro Arg His Phe Arg Pro Lys Gly Ala Gly Ser Thr Thr Val 230 235240 Lys Ile Val Leu Lys Glu Lys His Lys Lys Ala Cys Val His Gly 245 250255 Gly Lys Thr Tyr Ser His Gly Glu Val Trp His Pro Ala Phe Arg 260 265270 Ala Phe Gly Pro Leu Pro Cys Ile Leu Cys Thr Cys Glu Asp Gly 275 280285 Arg Gln Asp Cys Gln Arg Val Thr Cys Pro Thr Glu Tyr Pro Cys 290 295300 Arg His Pro Glu Lys Val Ala Gly Lys Cys Cys Lys Ile Cys Pro 305 310315 Glu Asp Lys Ala Asp Pro Gly His Ser Glu Ile Ser Ser Thr Arg 320 325330 Cys Pro Lys Ala Pro Gly Arg Val Leu Val His Thr Ser Val Ser 335 340345 Pro Ser Pro Asp Asn Leu Arg Arg Phe Ala Leu Glu His Glu Ala 350 355360 Ser Asp Leu Val Glu Ile Tyr Leu Trp Lys Leu Val Lys Asp Glu 365 370375 Glu Thr Glu Ala Gln Arg Gly Glu Val Pro Gly Pro Arg Pro His 380 385390 Ser Gln Asn Leu Pro Leu Asp Ser Asp Gln Glu Ser Gln Glu Ala 395 400405 Arg Leu Pro Glu Arg Gly Thr Ala Leu Pro Thr Ala Arg Trp Pro 410 415420 Pro Arg Arg Ser Leu Glu Arg Leu Pro Ser Pro Asp Pro Gly Ala 425 430435 Glu Gly His Gly Gln Ser Arg Gln Ser Asp Gln Asp Ile Thr Lys 440 445450 Thr 83 2052 DNA Homo Sapien 83 gacagctgtg tctcgatgga gtagactctcagaacagcgc agtttgccct 50 ccgctcacgc agagcctctc cgtggcttcc gcaccttgagcattaggcca 100 gttctcctct tctctctaat ccatccgtca cctctcctgt catccgtttc150 catgccgtga ggtccattca cagaacacat ccatggctct catgctcagt 200ttggttctga gtctcctcaa gctgggatca gggcagtggc aggtgtttgg 250 gccagacaagcctgtccagg ccttggtggg ggaggacgca gcattctcct 300 gtttcctgtc tcctaagaccaatgcagagg ccatggaagt gcggttcttc 350 aggggccagt tctctagcgt ggtccacctctacagggacg ggaaggacca 400 gccatttatg cagatgccac agtatcaagg caggacaaaactggtgaagg 450 attctattgc ggaggggcgc atctctctga ggctggaaaa cattactgtg500 ttggatgctg gcctctatgg gtgcaggatt agttcccagt cttactacca 550gaaggccatc tgggagctac aggtgtcagc actgggctca gttcctctca 600 tttccatcacgggatatgtt gatagagaca tccagctact ctgtcagtcc 650 tcgggctggt tcccccggcccacagcgaag tggaaaggtc cacaaggaca 700 ggatttgtcc acagactcca ggacaaacagagacatgcat ggcctgtttg 750 atgtggagat ctctctgacc gtccaagaga acgccgggagcatatcctgt 800 tccatgcggc atgctcatct gagccgagag gtggaatcca gggtacagat850 aggagatacc tttttcgagc ctatatcgtg gcacctggct accaaagtac 900tgggaatact ctgctgtggc ctattttttg gcattgttgg actgaagatt 950 ttcttctccaaattccagtg gaaaatccag gcggaactgg actggagaag 1000 aaagcacgga caggcagaattgagagacgc ccggaaacac gcagtggagg 1050 tgactctgga tccagagacg gctcacccgaagctctgcgt ttctgatctg 1100 aaaactgtaa cccatagaaa agctccccag gaggtgcctcactctgagaa 1150 gagatttaca aggaagagtg tggtggcttc tcagagtttc caagcaggga1200 aacattactg ggaggtggac ggaggacaca ataaaaggtg gcgcgtggga 1250gtgtgccggg atgatgtgga caggaggaag gagtacgtga ctttgtctcc 1300 cgatcatgggtactgggtcc tcagactgaa tggagaacat ttgtatttca 1350 cattaaatcc ccgttttatcagcgtcttcc ccaggacccc acctacaaaa 1400 ataggggtct tcctggacta tgagtgtgggaccatctcct tcttcaacat 1450 aaatgaccag tcccttattt ataccctgac atgtcggtttgaaggcttat 1500 tgaggcccta cattgagtat ccgtcctata atgagcaaaa tggaactccc1550 atagtcatct gcccagtcac ccaggaatca gagaaagagg cctcttggca 1600aagggcctct gcaatcccag agacaagcaa cagtgagtcc tcctcacagg 1650 caaccacgcccttcctcccc aggggtgaaa tgtaggatga atcacatccc 1700 acattcttct ttagggatattaaggtctct ctcccagatc caaagtcccg 1750 cagcagccgg ccaaggtggc ttccagatgaagggggactg gcctgtccac 1800 atgggagtca ggtgtcatgg ctgccctgag ctgggagggaagaaggctga 1850 cattacattt agtttgctct cactccatct ggctaagtga tcttgaaata1900 ccacctctca ggtgaagaac cgtcaggaat tcccatctca caggctgtgg 1950tgtagattaa gtagacaagg aatgtgaata atgcttagat cttattgatg 2000 acagagtgtatcctaatggt ttgttcatta tattacactt tcagtaaaaa 2050 aa 2052 84 500 PRT HomoSapien 84 Met Ala Leu Met Leu Ser Leu Val Leu Ser Leu Leu Lys Leu Gly 15 10 15 Ser Gly Gln Trp Gln Val Phe Gly Pro Asp Lys Pro Val Gln Ala 2025 30 Leu Val Gly Glu Asp Ala Ala Phe Ser Cys Phe Leu Ser Pro Lys 35 4045 Thr Asn Ala Glu Ala Met Glu Val Arg Phe Phe Arg Gly Gln Phe 50 55 60Ser Ser Val Val His Leu Tyr Arg Asp Gly Lys Asp Gln Pro Phe 65 70 75 MetGln Met Pro Gln Tyr Gln Gly Arg Thr Lys Leu Val Lys Asp 80 85 90 Ser IleAla Glu Gly Arg Ile Ser Leu Arg Leu Glu Asn Ile Thr 95 100 105 Val LeuAsp Ala Gly Leu Tyr Gly Cys Arg Ile Ser Ser Gln Ser 110 115 120 Tyr TyrGln Lys Ala Ile Trp Glu Leu Gln Val Ser Ala Leu Gly 125 130 135 Ser ValPro Leu Ile Ser Ile Thr Gly Tyr Val Asp Arg Asp Ile 140 145 150 Gln LeuLeu Cys Gln Ser Ser Gly Trp Phe Pro Arg Pro Thr Ala 155 160 165 Lys TrpLys Gly Pro Gln Gly Gln Asp Leu Ser Thr Asp Ser Arg 170 175 180 Thr AsnArg Asp Met His Gly Leu Phe Asp Val Glu Ile Ser Leu 185 190 195 Thr ValGln Glu Asn Ala Gly Ser Ile Ser Cys Ser Met Arg His 200 205 210 Ala HisLeu Ser Arg Glu Val Glu Ser Arg Val Gln Ile Gly Asp 215 220 225 Thr PhePhe Glu Pro Ile Ser Trp His Leu Ala Thr Lys Val Leu 230 235 240 Gly IleLeu Cys Cys Gly Leu Phe Phe Gly Ile Val Gly Leu Lys 245 250 255 Ile PhePhe Ser Lys Phe Gln Trp Lys Ile Gln Ala Glu Leu Asp 260 265 270 Trp ArgArg Lys His Gly Gln Ala Glu Leu Arg Asp Ala Arg Lys 275 280 285 His AlaVal Glu Val Thr Leu Asp Pro Glu Thr Ala His Pro Lys 290 295 300 Leu CysVal Ser Asp Leu Lys Thr Val Thr His Arg Lys Ala Pro 305 310 315 Gln GluVal Pro His Ser Glu Lys Arg Phe Thr Arg Lys Ser Val 320 325 330 Val AlaSer Gln Ser Phe Gln Ala Gly Lys His Tyr Trp Glu Val 335 340 345 Asp GlyGly His Asn Lys Arg Trp Arg Val Gly Val Cys Arg Asp 350 355 360 Asp ValAsp Arg Arg Lys Glu Tyr Val Thr Leu Ser Pro Asp His 365 370 375 Gly TyrTrp Val Leu Arg Leu Asn Gly Glu His Leu Tyr Phe Thr 380 385 390 Leu AsnPro Arg Phe Ile Ser Val Phe Pro Arg Thr Pro Pro Thr 395 400 405 Lys IleGly Val Phe Leu Asp Tyr Glu Cys Gly Thr Ile Ser Phe 410 415 420 Phe AsnIle Asn Asp Gln Ser Leu Ile Tyr Thr Leu Thr Cys Arg 425 430 435 Phe GluGly Leu Leu Arg Pro Tyr Ile Glu Tyr Pro Ser Tyr Asn 440 445 450 Glu GlnAsn Gly Thr Pro Ile Val Ile Cys Pro Val Thr Gln Glu 455 460 465 Ser GluLys Glu Ala Ser Trp Gln Arg Ala Ser Ala Ile Pro Glu 470 475 480 Thr SerAsn Ser Glu Ser Ser Ser Gln Ala Thr Thr Pro Phe Leu 485 490 495 Pro ArgGly Glu Met 500 85 1665 DNA Homo Sapien 85 aacagacgtt ccctcgcggccctggcacct ctaaccccag acatgctgct 50 gctgctgctg cccctgctct gggggagggagagggcggaa ggacagacaa 100 gtaaactgct gacgatgcag agttccgtga cggtgcaggaaggcctgtgt 150 gtccatgtgc cctgctcctt ctcctacccc tcgcatggct ggatttaccc200 tggcccagta gttcatggct actggttccg ggaaggggcc aatacagacc 250aggatgctcc agtggccaca aacaacccag ctcgggcagt gtgggaggag 300 actcgggaccgattccacct ccttggggac ccacatacca agaattgcac 350 cctgagcatc agagatgccagaagaagtga tgcggggaga tacttctttc 400 gtatggagaa aggaagtata aaatggaattataaacatca ccggctctct 450 gtgaatgtga cagccttgac ccacaggccc aacatcctcatcccaggcac 500 cctggagtcc ggctgccccc agaatctgac ctgctctgtg ccctgggcct550 gtgagcaggg gacaccccct atgatctcct ggatagggac ctccgtgtcc 600cccctggacc cctccaccac ccgctcctcg gtgctcaccc tcatcccaca 650 gccccaggaccatggcacca gcctcacctg tcaggtgacc ttccctgggg 700 ccagcgtgac cacgaacaagaccgtccatc tcaacgtgtc ctacccgcct 750 cagaacttga ccatgactgt cttccaaggagacggcacag tatccacagt 800 cttgggaaat ggctcatctc tgtcactccc agagggccagtctctgcgcc 850 tggtctgtgc agttgatgca gttgacagca atccccctgc caggctgagc900 ctgagctgga gaggcctgac cctgtgcccc tcacagccct caaacccggg 950ggtgctggag ctgccttggg tgcacctgag ggatgcagct gaattcacct 1000 gcagagctcagaaccctctc ggctctcagc aggtctacct gaacgtctcc 1050 ctgcagagca aagccacatcaggagtgact cagggggtgg tcgggggagc 1100 tggagccaca gccctggtct tcctgtccttctgcgtcatc ttcgttgtag 1150 tgaggtcctg caggaagaaa tcggcaaggc cagcagcgggcgtgggagat 1200 acgggcatag aggatgcaaa cgctgtcagg ggttcagcct ctcaggggcc1250 cctgactgaa ccttgggcag aagacagtcc cccagaccag cctcccccag 1300cttctgcccg ctcctcagtg ggggaaggag agctccagta tgcatccctc 1350 agcttccagatggtgaagcc ttgggactcg cggggacagg aggccactga 1400 caccgagtac tcggagatcaagatccacag atgagaaact gcagagactc 1450 accctgattg agggatcaca gcccctccaggcaagggaga agtcagaggc 1500 tgattcttgt agaattaaca gccctcaacg tgatgagctatgataacact 1550 atgaattatg tgcagagtga aaagcacaca ggctttagag tcaaagtatc1600 tcaaacctga atccacactg tgccctccct tttatttttt taactaaaag 1650acagacaaat tccta 1665 86 463 PRT Homo Sapien 86 Met Leu Leu Leu Leu LeuPro Leu Leu Trp Gly Arg Glu Arg Ala 1 5 10 15 Glu Gly Gln Thr Ser LysLeu Leu Thr Met Gln Ser Ser Val Thr 20 25 30 Val Gln Glu Gly Leu Cys ValHis Val Pro Cys Ser Phe Ser Tyr 35 40 45 Pro Ser His Gly Trp Ile Tyr ProGly Pro Val Val His Gly Tyr 50 55 60 Trp Phe Arg Glu Gly Ala Asn Thr AspGln Asp Ala Pro Val Ala 65 70 75 Thr Asn Asn Pro Ala Arg Ala Val Trp GluGlu Thr Arg Asp Arg 80 85 90 Phe His Leu Leu Gly Asp Pro His Thr Lys AsnCys Thr Leu Ser 95 100 105 Ile Arg Asp Ala Arg Arg Ser Asp Ala Gly ArgTyr Phe Phe Arg 110 115 120 Met Glu Lys Gly Ser Ile Lys Trp Asn Tyr LysHis His Arg Leu 125 130 135 Ser Val Asn Val Thr Ala Leu Thr His Arg ProAsn Ile Leu Ile 140 145 150 Pro Gly Thr Leu Glu Ser Gly Cys Pro Gln AsnLeu Thr Cys Ser 155 160 165 Val Pro Trp Ala Cys Glu Gln Gly Thr Pro ProMet Ile Ser Trp 170 175 180 Ile Gly Thr Ser Val Ser Pro Leu Asp Pro SerThr Thr Arg Ser 185 190 195 Ser Val Leu Thr Leu Ile Pro Gln Pro Gln AspHis Gly Thr Ser 200 205 210 Leu Thr Cys Gln Val Thr Phe Pro Gly Ala SerVal Thr Thr Asn 215 220 225 Lys Thr Val His Leu Asn Val Ser Tyr Pro ProGln Asn Leu Thr 230 235 240 Met Thr Val Phe Gln Gly Asp Gly Thr Val SerThr Val Leu Gly 245 250 255 Asn Gly Ser Ser Leu Ser Leu Pro Glu Gly GlnSer Leu Arg Leu 260 265 270 Val Cys Ala Val Asp Ala Val Asp Ser Asn ProPro Ala Arg Leu 275 280 285 Ser Leu Ser Trp Arg Gly Leu Thr Leu Cys ProSer Gln Pro Ser 290 295 300 Asn Pro Gly Val Leu Glu Leu Pro Trp Val HisLeu Arg Asp Ala 305 310 315 Ala Glu Phe Thr Cys Arg Ala Gln Asn Pro LeuGly Ser Gln Gln 320 325 330 Val Tyr Leu Asn Val Ser Leu Gln Ser Lys AlaThr Ser Gly Val 335 340 345 Thr Gln Gly Val Val Gly Gly Ala Gly Ala ThrAla Leu Val Phe 350 355 360 Leu Ser Phe Cys Val Ile Phe Val Val Val ArgSer Cys Arg Lys 365 370 375 Lys Ser Ala Arg Pro Ala Ala Gly Val Gly AspThr Gly Ile Glu 380 385 390 Asp Ala Asn Ala Val Arg Gly Ser Ala Ser GlnGly Pro Leu Thr 395 400 405 Glu Pro Trp Ala Glu Asp Ser Pro Pro Asp GlnPro Pro Pro Ala 410 415 420 Ser Ala Arg Ser Ser Val Gly Glu Gly Glu LeuGln Tyr Ala Ser 425 430 435 Leu Ser Phe Gln Met Val Lys Pro Trp Asp SerArg Gly Gln Glu 440 445 450 Ala Thr Asp Thr Glu Tyr Ser Glu Ile Lys IleHis Arg 455 460 87 1176 DNA Homo Sapien 87 agaaagctgc actctgttgagctccagggc gcagtggagg gagggagtga 50 aggagctctc tgtacccaag gaaagtgcagctgagactca gacaagatta 100 caatgaacca actcagcttc ctgctgtttc tcatagcgaccaccagagga 150 tggagtacag atgaggctaa tacttacttc aaggaatgga cctgttcttc200 gtctccatct ctgcccagaa gctgcaagga aatcaaagac gaatgtccta 250gtgcatttga tggcctgtat tttctccgca ctgagaatgg tgttatctac 300 cagaccttctgtgacatgac ctctgggggt ggcggctgga ccctggtggc 350 cagcgtgcat gagaatgacatgcgtgggaa gtgcacggtg ggcgatcgct 400 ggtccagtca gcagggcagc aaagcagactacccagaggg ggacggcaac 450 tgggccaact acaacacctt tggatctgca gaggcggccacgagcgatga 500 ctacaagaac cctggctact acgacatcca ggccaaggac ctgggcatct550 ggcacgtgcc caataagtcc cccatgcagc actggagaaa cagctccctg 600ctgaggtacc gcacggacac tggcttcctc cagacactgg gacataatct 650 gtttggcatctaccagaaat atccagtgaa atatggagaa ggaaagtgtt 700 ggactgacaa cggcccggtgatccctgtgg tctatgattt tggcgacgcc 750 cagaaaacag catcttatta ctcaccctatggccagcggg aattcactgc 800 gggatttgtt cagttcaggg tatttaataa cgagagagcagccaacgcct 850 tgtgtgctgg aatgagggtc accggatgta acactgagca tcactgcatt900 ggtggaggag gatactttcc agaggccagt ccccagcagt gtggagattt 950ttctggtttt gattggagtg gatatggaac tcatgttggt tacagcagca 1000 gccgtgagataactgaggca gctgtgcttc tattctatcg ttgagagttt 1050 tgtgggaggg aacccagacctctcctccca accatgagat cccaaggatg 1100 gagaacaact tacccagtag ctagaatgttaatggcagaa gagaaaacaa 1150 taaatcatat tgactcaaga aaaaaa 1176 88 313 PRTHomo Sapien 88 Met Asn Gln Leu Ser Phe Leu Leu Phe Leu Ile Ala Thr ThrArg 1 5 10 15 Gly Trp Ser Thr Asp Glu Ala Asn Thr Tyr Phe Lys Glu TrpThr 20 25 30 Cys Ser Ser Ser Pro Ser Leu Pro Arg Ser Cys Lys Glu Ile Lys35 40 45 Asp Glu Cys Pro Ser Ala Phe Asp Gly Leu Tyr Phe Leu Arg Thr 5055 60 Glu Asn Gly Val Ile Tyr Gln Thr Phe Cys Asp Met Thr Ser Gly 65 7075 Gly Gly Gly Trp Thr Leu Val Ala Ser Val His Glu Asn Asp Met 80 85 90Arg Gly Lys Cys Thr Val Gly Asp Arg Trp Ser Ser Gln Gln Gly 95 100 105Ser Lys Ala Asp Tyr Pro Glu Gly Asp Gly Asn Trp Ala Asn Tyr 110 115 120Asn Thr Phe Gly Ser Ala Glu Ala Ala Thr Ser Asp Asp Tyr Lys 125 130 135Asn Pro Gly Tyr Tyr Asp Ile Gln Ala Lys Asp Leu Gly Ile Trp 140 145 150His Val Pro Asn Lys Ser Pro Met Gln His Trp Arg Asn Ser Ser 155 160 165Leu Leu Arg Tyr Arg Thr Asp Thr Gly Phe Leu Gln Thr Leu Gly 170 175 180His Asn Leu Phe Gly Ile Tyr Gln Lys Tyr Pro Val Lys Tyr Gly 185 190 195Glu Gly Lys Cys Trp Thr Asp Asn Gly Pro Val Ile Pro Val Val 200 205 210Tyr Asp Phe Gly Asp Ala Gln Lys Thr Ala Ser Tyr Tyr Ser Pro 215 220 225Tyr Gly Gln Arg Glu Phe Thr Ala Gly Phe Val Gln Phe Arg Val 230 235 240Phe Asn Asn Glu Arg Ala Ala Asn Ala Leu Cys Ala Gly Met Arg 245 250 255Val Thr Gly Cys Asn Thr Glu His His Cys Ile Gly Gly Gly Gly 260 265 270Tyr Phe Pro Glu Ala Ser Pro Gln Gln Cys Gly Asp Phe Ser Gly 275 280 285Phe Asp Trp Ser Gly Tyr Gly Thr His Val Gly Tyr Ser Ser Ser 290 295 300Arg Glu Ile Thr Glu Ala Ala Val Leu Leu Phe Tyr Arg 305 310 89 759 DNAHomo Sapien 89 ctagatttgt cggcttgcgg ggagacttca ggagtcgctg tctctgaact 50tccagcctca gagaccgccg cccttgtccc cgagggccat gggccgggtc 100 tcagggcttgtgccctctcg cttcctgacg ctcctggcgc atctggtggt 150 cgtcatcacc ttattctggtcccgggacag caacatacag gcctgcctgc 200 ctctcacgtt cacccccgag gagtatgacaagcaggacat tcagctggtg 250 gccgcgctct ctgtcaccct gggcctcttt gcagtggagctggccggttt 300 cctctcagga gtctccatgt tcaacagcac ccagagcctc atctccattg350 gggctcactg tagtgcatcc gtggccctgt ccttcttcat attcgagcgt 400tgggagtgca ctacgtattg gtacattttt gtcttctgca gtgcccttcc 450 agctgtcactgaaatggctt tattcgtcac cgtctttggg ctgaaaaaga 500 aacccttctg attaccttcatgacgggaac ctaaggacga agcctacagg 550 ggcaagggcc gcttcgtatt cctggaagaaggaaggcata ggcttcggtt 600 ttcccctcgg aaactgcttc tgctggagga tatgtgttggaataattacg 650 tcttgagtct gggattatcc gcattgtatt tagtgctttg taataaaata700 tgttttgtag taacattaag acttatatac agttttaggg gacaattaaa 750 aaaaaaaaa759 90 140 PRT Homo Sapien 90 Met Gly Arg Val Ser Gly Leu Val Pro SerArg Phe Leu Thr Leu 1 5 10 15 Leu Ala His Leu Val Val Val Ile Thr LeuPhe Trp Ser Arg Asp 20 25 30 Ser Asn Ile Gln Ala Cys Leu Pro Leu Thr PheThr Pro Glu Glu 35 40 45 Tyr Asp Lys Gln Asp Ile Gln Leu Val Ala Ala LeuSer Val Thr 50 55 60 Leu Gly Leu Phe Ala Val Glu Leu Ala Gly Phe Leu SerGly Val 65 70 75 Ser Met Phe Asn Ser Thr Gln Ser Leu Ile Ser Ile Gly AlaHis 80 85 90 Cys Ser Ala Ser Val Ala Leu Ser Phe Phe Ile Phe Glu Arg Trp95 100 105 Glu Cys Thr Thr Tyr Trp Tyr Ile Phe Val Phe Cys Ser Ala Leu110 115 120 Pro Ala Val Thr Glu Met Ala Leu Phe Val Thr Val Phe Gly Leu125 130 135 Lys Lys Lys Pro Phe 140 91 1871 DNA Homo Sapien 91ctgggacccc gaaaagagaa ggggagagcg aggggacgag agcggaggag 50 gaagatgcaactgactcgct gctgcttcgt gttcctggtg cagggtagcc 100 tctatctggt catctgtggccaggatgatg gtcctcccgg ctcagaggac 150 cctgagcgtg atgaccacga gggccagccccggccccggg tgcctcggaa 200 gcggggccac atctcaccta agtcccgccc catggccaattccactctcc 250 tagggctgct ggccccgcct ggggaggctt ggggcattct tgggcagccc300 cccaaccgcc cgaaccacag ccccccaccc tcagccaagg tgaagaaaat 350ctttggctgg ggcgacttct actccaacat caagacggtg gccctgaacc 400 tgctcgtcacagggaagatt gtggaccatg gcaatgggac cttcagcgtc 450 cacttccaac acaatgccacaggccaggga aacatctcca tcagcctcgt 500 gccccccagt aaagctgtag agttccaccaggaacagcag atcttcatcg 550 aagccaaggc ctccaaaatc ttcaactgcc ggatggagtgggagaaggta 600 gaacggggcc gccggacctc gctttgcacc cacgacccag ccaagatctg650 ctcccgagac cacgctcaga gctcagccac ctggagctgc tcccagccct 700tcaaagtcgt ctgtgtctac atcgccttct acagcacgga ctatcggctg 750 gtccagaaggtgtgcccaga ttacaactac catagtgata ccccctacta 800 cccatctggg tgacccggggcaggccacag aggccaggcc agggctggaa 850 ggacaggcct gcccatgcag gagaccatctggacaccggg cagggaaggg 900 gttgggcctc aggcagggag gggggtggag acgaggagatgccaagtggg 950 gccagggcca agtctcaagt ggcagagaaa gggtcccaag tgctggtccc1000 aacctgaagc tgtggagtga ctagatcaca ggagcactgg aggaggagtg 1050ggctctctgt gcagcctcac agggctttgc cacggagcca cagagagatg 1100 ctgggtccccgaggcctgtg ggcaggccga tcagtgtggc cccagatcaa 1150 gtcatgggag gaagctaagcccttggttct tgccatcctg aggaaagata 1200 gcaacaggga gggggagatt tcatcagtgtggacagcctg tcaacttagg 1250 atggatggct gagagggctt cctaggagcc agtcagcagggtggggtggg 1300 gccagaggag ctctccagcc ctgcctagtg ggcgccctga gccccttgtc1350 gtgtgctgag catggcatga ggctgaagtg gcaaccctgg ggtctttgat 1400gtcttgacag attgaccatc tgtctccagc caggccaccc ctttccaaaa 1450 ttccctcttctgccagtact ccccctgtac cacccattgc tgatggcaca 1500 cccatcctta agctaagacaggacgattgt ggtcctccca cactaaggcc 1550 acagcccatc cgcgtgctgt gtgtccctcttccaccccaa cccctgctgg 1600 ctcctctggg agcatccatg tcccggagag gggtccctcaacagtcagcc 1650 tcacctgtca gaccggggtt ctcccggatc tggatggcgc cgccctctca1700 gcagcgggca cgggtggggc ggggccgggc cgcagagcat gtgctggatc 1750tgttctgtgt gtctgtctgt gggtgggggg aggggaggga agtcttgtga 1800 aaccgctgattgctgacttt tgtgtgaaga atcgtgttct tggagcagga 1850 aataaagctt gccccggggc a1871 92 252 PRT Homo Sapien 92 Met Gln Leu Thr Arg Cys Cys Phe Val PheLeu Val Gln Gly Ser 1 5 10 15 Leu Tyr Leu Val Ile Cys Gly Gln Asp AspGly Pro Pro Gly Ser 20 25 30 Glu Asp Pro Glu Arg Asp Asp His Glu Gly GlnPro Arg Pro Arg 35 40 45 Val Pro Arg Lys Arg Gly His Ile Ser Pro Lys SerArg Pro Met 50 55 60 Ala Asn Ser Thr Leu Leu Gly Leu Leu Ala Pro Pro GlyGlu Ala 65 70 75 Trp Gly Ile Leu Gly Gln Pro Pro Asn Arg Pro Asn His SerPro 80 85 90 Pro Pro Ser Ala Lys Val Lys Lys Ile Phe Gly Trp Gly Asp Phe95 100 105 Tyr Ser Asn Ile Lys Thr Val Ala Leu Asn Leu Leu Val Thr Gly110 115 120 Lys Ile Val Asp His Gly Asn Gly Thr Phe Ser Val His Phe Gln125 130 135 His Asn Ala Thr Gly Gln Gly Asn Ile Ser Ile Ser Leu Val Pro140 145 150 Pro Ser Lys Ala Val Glu Phe His Gln Glu Gln Gln Ile Phe Ile155 160 165 Glu Ala Lys Ala Ser Lys Ile Phe Asn Cys Arg Met Glu Trp Glu170 175 180 Lys Val Glu Arg Gly Arg Arg Thr Ser Leu Cys Thr His Asp Pro185 190 195 Ala Lys Ile Cys Ser Arg Asp His Ala Gln Ser Ser Ala Thr Trp200 205 210 Ser Cys Ser Gln Pro Phe Lys Val Val Cys Val Tyr Ile Ala Phe215 220 225 Tyr Ser Thr Asp Tyr Arg Leu Val Gln Lys Val Cys Pro Asp Tyr230 235 240 Asn Tyr His Ser Asp Thr Pro Tyr Tyr Pro Ser Gly 245 250 93902 DNA Homo Sapien 93 cggtggccat gactgcggcc gtgttcttcg gctgcgccttcattgccttc 50 gggcctgcgc tcgcccttta tgtcttcacc atcgccatcg agccgttgcg 100tatcatcttc ctcatcgccg gagctttctt ctggttggtg tctctactga 150 tttcgtcccttgtttggttc atggcaagag tcattattga caacaaagat 200 ggaccaacac agaaatatctgctgatcttt ggagcgtttg tctctgtcta 250 tatccaagaa atgttccgat ttgcatattataaactctta aaaaaagcca 300 gtgaaggttt gaagagtata aacccaggtg agacagcaccctctatgcga 350 ctgctggcct atgtttctgg cttgggcttt ggaatcatga gtggagtatt400 ttcctttgtg aataccctat ctgactcctt ggggccaggc acagtgggca 450ttcatggaga ttctcctcaa ttcttccttt attcagcttt catgacgctg 500 gtcattatcttgctgcatgt attctggggc attgtatttt ttgatggctg 550 tgagaagaaa aagtggggcatcctccttat cgttctcctg acccacctgc 600 tggtgtcagc ccagaccttc ataagttcttattatggaat aaacctggcg 650 tcagcattta taatcctggt gctcatgggc acctgggcattcttagctgc 700 gggaggcagc tgccgaagcc tgaaactctg cctgctctgc caagacaaga750 actttcttct ttacaaccag cgctccagat aacctcaggg aaccagcact 800tcccaaaccg cagactacat ctttagagga agcacaactg tgcctttttc 850 tgaaaatccctttttctggt ggaattgaga aagaaataaa actatgcaga 900 ta 902 94 257 PRT HomoSapien 94 Met Thr Ala Ala Val Phe Phe Gly Cys Ala Phe Ile Ala Phe Gly 15 10 15 Pro Ala Leu Ala Leu Tyr Val Phe Thr Ile Ala Ile Glu Pro Leu 2025 30 Arg Ile Ile Phe Leu Ile Ala Gly Ala Phe Phe Trp Leu Val Ser 35 4045 Leu Leu Ile Ser Ser Leu Val Trp Phe Met Ala Arg Val Ile Ile 50 55 60Asp Asn Lys Asp Gly Pro Thr Gln Lys Tyr Leu Leu Ile Phe Gly 65 70 75 AlaPhe Val Ser Val Tyr Ile Gln Glu Met Phe Arg Phe Ala Tyr 80 85 90 Tyr LysLeu Leu Lys Lys Ala Ser Glu Gly Leu Lys Ser Ile Asn 95 100 105 Pro GlyGlu Thr Ala Pro Ser Met Arg Leu Leu Ala Tyr Val Ser 110 115 120 Gly LeuGly Phe Gly Ile Met Ser Gly Val Phe Ser Phe Val Asn 125 130 135 Thr LeuSer Asp Ser Leu Gly Pro Gly Thr Val Gly Ile His Gly 140 145 150 Asp SerPro Gln Phe Phe Leu Tyr Ser Ala Phe Met Thr Leu Val 155 160 165 Ile IleLeu Leu His Val Phe Trp Gly Ile Val Phe Phe Asp Gly 170 175 180 Cys GluLys Lys Lys Trp Gly Ile Leu Leu Ile Val Leu Leu Thr 185 190 195 His LeuLeu Val Ser Ala Gln Thr Phe Ile Ser Ser Tyr Tyr Gly 200 205 210 Ile AsnLeu Ala Ser Ala Phe Ile Ile Leu Val Leu Met Gly Thr 215 220 225 Trp AlaPhe Leu Ala Ala Gly Gly Ser Cys Arg Ser Leu Lys Leu 230 235 240 Cys LeuLeu Cys Gln Asp Lys Asn Phe Leu Leu Tyr Asn Gln Arg 245 250 255 Ser Arg95 1073 DNA Homo Sapien 95 aatttttcac cagagtaaac ttgagaaacc aactggaccttgagtattgt 50 acattttgcc tcgtggaccc aaaggtagca atctgaaaca tgaggagtac 100gattctactg ttttgtcttc taggatcaac tcggtcatta ccacagctca 150 aacctgctttgggactccct cccacaaaac tggctccgga tcagggaaca 200 ctaccaaacc aacagcagtcaaatcaggtc tttccttctt taagtctgat 250 accattaaca cagatgctca cactggggccagatctgcat ctgttaaatc 300 ctgctgcagg aatgacacct ggtacccaga cccacccattgaccctggga 350 gggttgaatg tacaacagca actgcaccca catgtgttac caatttttgt400 cacacaactt ggagcccagg gcactatcct aagctcagag gaattgccac 450aaatcttcac gagcctcatc atccattcct tgttcccggg aggcatcctg 500 cccaccagtcaggcaggggc taatccagat gtccaggatg gaagccttcc 550 agcaggagga gcaggtgtaaatcctgccac ccagggaacc ccagcaggcc 600 gcctcccaac tcccagtggc acagatgacgactttgcagt gaccacccct 650 gcaggcatcc aaaggagcac acatgccatc gaggaagccaccacagaatc 700 agcaaatgga attcagtaag ctgtttcaaa ttttttcaac taagctgcct750 cgaatttggt gatacatgtg aatctttatc attgattata ttatggaata 800gattgagaca cattggatag tcttagaaga aattaattct taatttacct 850 gaaaatattcttgaaatttc agaaaatatg ttctatgtag agaatcccaa 900 cttttaaaaa caataattcaatggataaat ctgtctttga aatataacat 950 tatgctgcct ggatgatatg catattaaaacatatttgga aaactggaaa 1000 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaaaaaaaaaaaa 1050 aaaaaaaaaa aaaaaaaaaa aaa 1073 96 209 PRT Homo Sapien 96Met Arg Ser Thr Ile Leu Leu Phe Cys Leu Leu Gly Ser Thr Arg 1 5 10 15Ser Leu Pro Gln Leu Lys Pro Ala Leu Gly Leu Pro Pro Thr Lys 20 25 30 LeuAla Pro Asp Gln Gly Thr Leu Pro Asn Gln Gln Gln Ser Asn 35 40 45 Gln ValPhe Pro Ser Leu Ser Leu Ile Pro Leu Thr Gln Met Leu 50 55 60 Thr Leu GlyPro Asp Leu His Leu Leu Asn Pro Ala Ala Gly Met 65 70 75 Thr Pro Gly ThrGln Thr His Pro Leu Thr Leu Gly Gly Leu Asn 80 85 90 Val Gln Gln Gln LeuHis Pro His Val Leu Pro Ile Phe Val Thr 95 100 105 Gln Leu Gly Ala GlnGly Thr Ile Leu Ser Ser Glu Glu Leu Pro 110 115 120 Gln Ile Phe Thr SerLeu Ile Ile His Ser Leu Phe Pro Gly Gly 125 130 135 Ile Leu Pro Thr SerGln Ala Gly Ala Asn Pro Asp Val Gln Asp 140 145 150 Gly Ser Leu Pro AlaGly Gly Ala Gly Val Asn Pro Ala Thr Gln 155 160 165 Gly Thr Pro Ala GlyArg Leu Pro Thr Pro Ser Gly Thr Asp Asp 170 175 180 Asp Phe Ala Val ThrThr Pro Ala Gly Ile Gln Arg Ser Thr His 185 190 195 Ala Ile Glu Glu AlaThr Thr Glu Ser Ala Asn Gly Ile Gln 200 205 97 2848 DNA Homo Sapien 97gctcaagtgc cctgccttgc cccacccagc ccagcctggc cagagccccc 50 tggagaaggagctctcttct tgcttggcag ctggaccaag ggagccagtc 100 ttgggcgctg gagggcctgtcctgaccatg gtccctgcct ggctgtggct 150 gctttgtgtc tccgtccccc aggctctccccaaggcccag cctgcagagc 200 tgtctgtgga agttccagaa aactatggtg gaaatttccctttatacctg 250 accaagttgc cgctgccccg tgagggggct gaaggccaga tcgtgctgtc300 aggggactca ggcaaggcaa ctgagggccc atttgctatg gatccagatt 350ctggcttcct gctggtgacc agggccctgg accgagagga gcaggcagag 400 taccagctacaggtcaccct ggagatgcag gatggacatg tcttgtgggg 450 tccacagcct gtgcttgtgcacgtgaagga tgagaatgac caggtgcccc 500 atttctctca agccatctac agagctcggctgagccgggg taccaggcct 550 ggcatcccct tcctcttcct tgaggcttca gaccgggatgagccaggcac 600 agccaactcg gatcttcgat tccacatcct gagccaggct ccagcccagc650 cttccccaga catgttccag ctggagcctc ggctgggggc tctggccctc 700agccccaagg ggagcaccag ccttgaccac gccctggaga ggacctacca 750 gctgttggtacaggtcaagg acatgggtga ccaggcctca ggccaccagg 800 ccactgccac cgtggaagtctccatcatag agagcacctg ggtgtcccta 850 gagcctatcc acctggcaga gaatctcaaagtcctatacc cgcaccacat 900 ggcccaggta cactggagtg ggggtgatgt gcactatcacctggagagcc 950 atcccccggg accctttgaa gtgaatgcag agggaaacct ctacgtgacc1000 agagagctgg acagagaagc ccaggctgag tacctgctcc aggtgcgggc 1050tcagaattcc catggcgagg actatgcggc ccctctggag ctgcacgtgc 1100 tggtgatggatgagaatgac aacgtgccta tctgccctcc ccgtgacccc 1150 acagtcagca tccctgagctcagtccacca ggtactgaag tgactagact 1200 gtcagcagag gatgcagatg cccccggctcccccaattcc cacgttgtgt 1250 atcagctcct gagccctgag cctgaggatg gggtagaggggagagccttc 1300 caggtggacc ccacttcagg cagtgtgacg ctgggggtgc tcccactccg1350 agcaggccag aacatcctgc ttctggtgct ggccatggac ctggcaggcg 1400cagagggtgg cttcagcagc acgtgtgaag tcgaagtcgc agtcacagat 1450 atcaatgatcacgcccctga gttcatcact tcccagattg ggcctataag 1500 cctccctgag gatgtggagcccgggactct ggtggccatg ctaacagcca 1550 ttgatgctga cctcgagccc gccttccgcctcatggattt tgccattgag 1600 aggggagaca cagaagggac ttttggcctg gattgggagccagactctgg 1650 gcatgttaga ctcagactct gcaagaacct cagttatgag gcagctccaa1700 gtcatgaggt ggtggtggtg gtgcagagtg tggcgaagct ggtggggcca 1750ggcccaggcc ctggagccac cgccacggtg actgtgctag tggagagagt 1800 gatgccaccccccaagttgg accaggagag ctacgaggcc agtgtcccca 1850 tcagtgcccc agccggctctttcctgctga ccatccagcc ctccgacccc 1900 atcagccgaa ccctcaggtt ctccctagtcaatgactcag agggctggct 1950 ctgcattgag aaattctccg gggaggtgca caccgcccagtccctgcagg 2000 gcgcccagcc tggggacacc tacacggtgc ttgtggaggc ccaggataca2050 gccctgactc ttgcccctgt gccctcccaa tacctctgca caccccgcca 2100agaccatggc ttgatcgtga gtggacccag caaggacccc gatctggcca 2150 gtgggcacggtccctacagc ttcacccttg gtcccaaccc cacggtgcaa 2200 cgggattggc gcctccagactctcaatggt tcccatgcct acctcacctt 2250 ggccctgcat tgggtggagc cacgtgaacacataatcccc gtggtggtca 2300 gccacaatgc ccagatgtgg cagctcctgg ttcgagtgatcgtgtgtcgc 2350 tgcaacgtgg aggggcagtg catgcgcaag gtgggccgca tgaagggcat2400 gcccacgaag ctgtcggcag tgggcatcct tgtaggcacc ctggtagcaa 2450taggaatctt cctcatcctc attttcaccc actggaccat gtcaaggaag 2500 aaggacccggatcaaccagc agacagcgtg cccctgaagg cgactgtctg 2550 aatggcccag gcagctctagctgggagctt ggcctctggc tccatctgag 2600 tcccctggga gagagcccag cacccaagatccagcagggg acaggacaga 2650 gtagaagccc ctccatctgc cctggggtgg aggcaccatcaccatcacca 2700 ggcatgtctg cagagcctgg acaccaactt tatggactgc ccatgggagt2750 gctccaaatg tcagggtgtt tgcccaataa taaagcccca gagaactggg 2800ctgggcccta tgggaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaag 2848 98 807 PRTHomo Sapien 98 Met Val Pro Ala Trp Leu Trp Leu Leu Cys Val Ser Val ProGln 1 5 10 15 Ala Leu Pro Lys Ala Gln Pro Ala Glu Leu Ser Val Glu ValPro 20 25 30 Glu Asn Tyr Gly Gly Asn Phe Pro Leu Tyr Leu Thr Lys Leu Pro35 40 45 Leu Pro Arg Glu Gly Ala Glu Gly Gln Ile Val Leu Ser Gly Asp 5055 60 Ser Gly Lys Ala Thr Glu Gly Pro Phe Ala Met Asp Pro Asp Ser 65 7075 Gly Phe Leu Leu Val Thr Arg Ala Leu Asp Arg Glu Glu Gln Ala 80 85 90Glu Tyr Gln Leu Gln Val Thr Leu Glu Met Gln Asp Gly His Val 95 100 105Leu Trp Gly Pro Gln Pro Val Leu Val His Val Lys Asp Glu Asn 110 115 120Asp Gln Val Pro His Phe Ser Gln Ala Ile Tyr Arg Ala Arg Leu 125 130 135Ser Arg Gly Thr Arg Pro Gly Ile Pro Phe Leu Phe Leu Glu Ala 140 145 150Ser Asp Arg Asp Glu Pro Gly Thr Ala Asn Ser Asp Leu Arg Phe 155 160 165His Ile Leu Ser Gln Ala Pro Ala Gln Pro Ser Pro Asp Met Phe 170 175 180Gln Leu Glu Pro Arg Leu Gly Ala Leu Ala Leu Ser Pro Lys Gly 185 190 195Ser Thr Ser Leu Asp His Ala Leu Glu Arg Thr Tyr Gln Leu Leu 200 205 210Val Gln Val Lys Asp Met Gly Asp Gln Ala Ser Gly His Gln Ala 215 220 225Thr Ala Thr Val Glu Val Ser Ile Ile Glu Ser Thr Trp Val Ser 230 235 240Leu Glu Pro Ile His Leu Ala Glu Asn Leu Lys Val Leu Tyr Pro 245 250 255His His Met Ala Gln Val His Trp Ser Gly Gly Asp Val His Tyr 260 265 270His Leu Glu Ser His Pro Pro Gly Pro Phe Glu Val Asn Ala Glu 275 280 285Gly Asn Leu Tyr Val Thr Arg Glu Leu Asp Arg Glu Ala Gln Ala 290 295 300Glu Tyr Leu Leu Gln Val Arg Ala Gln Asn Ser His Gly Glu Asp 305 310 315Tyr Ala Ala Pro Leu Glu Leu His Val Leu Val Met Asp Glu Asn 320 325 330Asp Asn Val Pro Ile Cys Pro Pro Arg Asp Pro Thr Val Ser Ile 335 340 345Pro Glu Leu Ser Pro Pro Gly Thr Glu Val Thr Arg Leu Ser Ala 350 355 360Glu Asp Ala Asp Ala Pro Gly Ser Pro Asn Ser His Val Val Tyr 365 370 375Gln Leu Leu Ser Pro Glu Pro Glu Asp Gly Val Glu Gly Arg Ala 380 385 390Phe Gln Val Asp Pro Thr Ser Gly Ser Val Thr Leu Gly Val Leu 395 400 405Pro Leu Arg Ala Gly Gln Asn Ile Leu Leu Leu Val Leu Ala Met 410 415 420Asp Leu Ala Gly Ala Glu Gly Gly Phe Ser Ser Thr Cys Glu Val 425 430 435Glu Val Ala Val Thr Asp Ile Asn Asp His Ala Pro Glu Phe Ile 440 445 450Thr Ser Gln Ile Gly Pro Ile Ser Leu Pro Glu Asp Val Glu Pro 455 460 465Gly Thr Leu Val Ala Met Leu Thr Ala Ile Asp Ala Asp Leu Glu 470 475 480Pro Ala Phe Arg Leu Met Asp Phe Ala Ile Glu Arg Gly Asp Thr 485 490 495Glu Gly Thr Phe Gly Leu Asp Trp Glu Pro Asp Ser Gly His Val 500 505 510Arg Leu Arg Leu Cys Lys Asn Leu Ser Tyr Glu Ala Ala Pro Ser 515 520 525His Glu Val Val Val Val Val Gln Ser Val Ala Lys Leu Val Gly 530 535 540Pro Gly Pro Gly Pro Gly Ala Thr Ala Thr Val Thr Val Leu Val 545 550 555Glu Arg Val Met Pro Pro Pro Lys Leu Asp Gln Glu Ser Tyr Glu 560 565 570Ala Ser Val Pro Ile Ser Ala Pro Ala Gly Ser Phe Leu Leu Thr 575 580 585Ile Gln Pro Ser Asp Pro Ile Ser Arg Thr Leu Arg Phe Ser Leu 590 595 600Val Asn Asp Ser Glu Gly Trp Leu Cys Ile Glu Lys Phe Ser Gly 605 610 615Glu Val His Thr Ala Gln Ser Leu Gln Gly Ala Gln Pro Gly Asp 620 625 630Thr Tyr Thr Val Leu Val Glu Ala Gln Asp Thr Ala Leu Thr Leu 635 640 645Ala Pro Val Pro Ser Gln Tyr Leu Cys Thr Pro Arg Gln Asp His 650 655 660Gly Leu Ile Val Ser Gly Pro Ser Lys Asp Pro Asp Leu Ala Ser 665 670 675Gly His Gly Pro Tyr Ser Phe Thr Leu Gly Pro Asn Pro Thr Val 680 685 690Gln Arg Asp Trp Arg Leu Gln Thr Leu Asn Gly Ser His Ala Tyr 695 700 705Leu Thr Leu Ala Leu His Trp Val Glu Pro Arg Glu His Ile Ile 710 715 720Pro Val Val Val Ser His Asn Ala Gln Met Trp Gln Leu Leu Val 725 730 735Arg Val Ile Val Cys Arg Cys Asn Val Glu Gly Gln Cys Met Arg 740 745 750Lys Val Gly Arg Met Lys Gly Met Pro Thr Lys Leu Ser Ala Val 755 760 765Gly Ile Leu Val Gly Thr Leu Val Ala Ile Gly Ile Phe Leu Ile 770 775 780Leu Ile Phe Thr His Trp Thr Met Ser Arg Lys Lys Asp Pro Asp 785 790 795Gln Pro Ala Asp Ser Val Pro Leu Lys Ala Thr Val 800 805 99 2436 DNA HomoSapien 99 ggctgaccgt gctacattgc ctggaggaag cctaaggaac ccaggcatcc 50agctgcccac gcctgagtcc aagattcttc ccaggaacac aaacgtagga 100 gacccacgctcctggaagca ccagccttta tctcttcacc ttcaagtccc 150 ctttctcaag aatcctctgttctttgccct ctaaagtctt ggtacatcta 200 ggacccaggc atcttgcttt ccagccacaaagagacagat gaagatgcag 250 aaaggaaatg ttctccttat gtttggtcta ctattgcatttagaagctgc 300 aacaaattcc aatgagacta gcacctctgc caacactgga tccagtgtga350 tctccagtgg agccagcaca gccaccaact ctgggtccag tgtgacctcc 400agtggggtca gcacagccac catctcaggg tccagcgtga cctccaatgg 450 ggtcagcatagtcaccaact ctgagttcca tacaacctcc agtgggatca 500 gcacagccac caactctgagttcagcacag cgtccagtgg gatcagcata 550 gccaccaact ctgagtccag cacaacctccagtggggcca gcacagccac 600 caactctgag tccagcacac cctccagtgg ggccagcacagtcaccaact 650 ctgggtccag tgtgacctcc agtggagcca gcactgccac caactctgag700 tccagcacag tgtccagtag ggccagcact gccaccaact ctgagtctag 750cacactctcc agtggggcca gcacagccac caactctgac tccagcacaa 800 cctccagtggggctagcaca gccaccaact ctgagtccag cacaacctcc 850 agtggggcca gcacagccaccaactctgag tccagcacag tgtccagtag 900 ggccagcact gccaccaact ctgagtccagcacaacctcc agtggggcca 950 gcacagccac caactctgag tccagaacga cctccaatggggctggcaca 1000 gccaccaact ctgagtccag cacgacctcc agtggggcca gcacagccac1050 caactctgac tccagcacag tgtccagtgg ggccagcact gccaccaact 1100ctgagtccag cacgacctcc agtggggcca gcacagccac caactctgag 1150 tccagcacgacctccagtgg ggctagcaca gccaccaact ctgactccag 1200 cacaacctcc agtggggccggcacagccac caactctgag tccagcacag 1250 tgtccagtgg gatcagcaca gtcaccaattctgagtccag cacaccctcc 1300 agtggggcca acacagccac caactctgag tccagtacgacctccagtgg 1350 ggccaacaca gccaccaact ctgagtccag cacagtgtcc agtggggcca1400 gcactgccac caactctgag tccagcacaa cctccagtgg ggtcagcaca 1450gccaccaact ctgagtccag cacaacctcc agtggggcta gcacagccac 1500 caactctgactccagcacaa cctccagtga ggccagcaca gccaccaact 1550 ctgagtctag cacagtgtccagtgggatca gcacagtcac caattctgag 1600 tccagcacaa cctccagtgg ggccaacacagccaccaact ctgggtccag 1650 tgtgacctct gcaggctctg gaacagcagc tctgactggaatgcacacaa 1700 cttcccatag tgcatctact gcagtgagtg aggcaaagcc tggtgggtcc1750 ctggtgccgt gggaaatctt cctcatcacc ctggtctcgg ttgtggcggc 1800cgtggggctc tttgctgggc tcttcttctg tgtgagaaac agcctgtccc 1850 tgagaaacacctttaacaca gctgtctacc accctcatgg cctcaaccat 1900 ggccttggtc caggccctggagggaatcat ggagcccccc acaggcccag 1950 gtggagtcct aactggttct ggaggagaccagtatcatcg atagccatgg 2000 agatgagcgg gaggaacagc gggccctgag cagccccggaagcaagtgcc 2050 gcattcttca ggaaggaaga gacctgggca cccaagacct ggtttccttt2100 cattcatccc aggagacccc tcccagcttt gtttgagatc ctgaaaatct 2150tgaagaaggt attcctcacc tttcttgcct ttaccagaca ctggaaagag 2200 aatactatattgctcattta gctaagaaat aaatacatct catctaacac 2250 acacgacaaa gagaagctgtgcttgccccg gggtgggtat ctagctctga 2300 gatgaactca gttataggag aaaacctccatgctggactc catctggcat 2350 tcaaaatctc cacagtaaaa tccaaagacc tcaaaaaaaaaaaaaaaaaa 2400 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaa 2436 100 596 PRTHomo Sapien 100 Met Lys Met Gln Lys Gly Asn Val Leu Leu Met Phe Gly LeuLeu 1 5 10 15 Leu His Leu Glu Ala Ala Thr Asn Ser Asn Glu Thr Ser ThrSer 20 25 30 Ala Asn Thr Gly Ser Ser Val Ile Ser Ser Gly Ala Ser Thr Ala35 40 45 Thr Asn Ser Gly Ser Ser Val Thr Ser Ser Gly Val Ser Thr Ala 5055 60 Thr Ile Ser Gly Ser Ser Val Thr Ser Asn Gly Val Ser Ile Val 65 7075 Thr Asn Ser Glu Phe His Thr Thr Ser Ser Gly Ile Ser Thr Ala 80 85 90Thr Asn Ser Glu Phe Ser Thr Ala Ser Ser Gly Ile Ser Ile Ala 95 100 105Thr Asn Ser Glu Ser Ser Thr Thr Ser Ser Gly Ala Ser Thr Ala 110 115 120Thr Asn Ser Glu Ser Ser Thr Pro Ser Ser Gly Ala Ser Thr Val 125 130 135Thr Asn Ser Gly Ser Ser Val Thr Ser Ser Gly Ala Ser Thr Ala 140 145 150Thr Asn Ser Glu Ser Ser Thr Val Ser Ser Arg Ala Ser Thr Ala 155 160 165Thr Asn Ser Glu Ser Ser Thr Leu Ser Ser Gly Ala Ser Thr Ala 170 175 180Thr Asn Ser Asp Ser Ser Thr Thr Ser Ser Gly Ala Ser Thr Ala 185 190 195Thr Asn Ser Glu Ser Ser Thr Thr Ser Ser Gly Ala Ser Thr Ala 200 205 210Thr Asn Ser Glu Ser Ser Thr Val Ser Ser Arg Ala Ser Thr Ala 215 220 225Thr Asn Ser Glu Ser Ser Thr Thr Ser Ser Gly Ala Ser Thr Ala 230 235 240Thr Asn Ser Glu Ser Arg Thr Thr Ser Asn Gly Ala Gly Thr Ala 245 250 255Thr Asn Ser Glu Ser Ser Thr Thr Ser Ser Gly Ala Ser Thr Ala 260 265 270Thr Asn Ser Asp Ser Ser Thr Val Ser Ser Gly Ala Ser Thr Ala 275 280 285Thr Asn Ser Glu Ser Ser Thr Thr Ser Ser Gly Ala Ser Thr Ala 290 295 300Thr Asn Ser Glu Ser Ser Thr Thr Ser Ser Gly Ala Ser Thr Ala 305 310 315Thr Asn Ser Asp Ser Ser Thr Thr Ser Ser Gly Ala Gly Thr Ala 320 325 330Thr Asn Ser Glu Ser Ser Thr Val Ser Ser Gly Ile Ser Thr Val 335 340 345Thr Asn Ser Glu Ser Ser Thr Pro Ser Ser Gly Ala Asn Thr Ala 350 355 360Thr Asn Ser Glu Ser Ser Thr Thr Ser Ser Gly Ala Asn Thr Ala 365 370 375Thr Asn Ser Glu Ser Ser Thr Val Ser Ser Gly Ala Ser Thr Ala 380 385 390Thr Asn Ser Glu Ser Ser Thr Thr Ser Ser Gly Val Ser Thr Ala 395 400 405Thr Asn Ser Glu Ser Ser Thr Thr Ser Ser Gly Ala Ser Thr Ala 410 415 420Thr Asn Ser Asp Ser Ser Thr Thr Ser Ser Glu Ala Ser Thr Ala 425 430 435Thr Asn Ser Glu Ser Ser Thr Val Ser Ser Gly Ile Ser Thr Val 440 445 450Thr Asn Ser Glu Ser Ser Thr Thr Ser Ser Gly Ala Asn Thr Ala 455 460 465Thr Asn Ser Gly Ser Ser Val Thr Ser Ala Gly Ser Gly Thr Ala 470 475 480Ala Leu Thr Gly Met His Thr Thr Ser His Ser Ala Ser Thr Ala 485 490 495Val Ser Glu Ala Lys Pro Gly Gly Ser Leu Val Pro Trp Glu Ile 500 505 510Phe Leu Ile Thr Leu Val Ser Val Val Ala Ala Val Gly Leu Phe 515 520 525Ala Gly Leu Phe Phe Cys Val Arg Asn Ser Leu Ser Leu Arg Asn 530 535 540Thr Phe Asn Thr Ala Val Tyr His Pro His Gly Leu Asn His Gly 545 550 555Leu Gly Pro Gly Pro Gly Gly Asn His Gly Ala Pro His Arg Pro 560 565 570Arg Trp Ser Pro Asn Trp Phe Trp Arg Arg Pro Val Ser Ser Ile 575 580 585Ala Met Glu Met Ser Gly Arg Asn Ser Gly Pro 590 595 101 1728 DNA HomoSapien 101 ggccggacgc ctccgcgtta cgggatgaat taacggcggg ttccgcacgg 50aggttgtgac ccctacggag ccccagcttg cccacgcacc ccactcggcg 100 tcgcgcggcgtgccctgctt gtcacaggtg ggaggctgga actatcaggc 150 tgaaaaacag agtgggtactctcttctggg aagctggcaa caaatggatg 200 atgtgatata tgcattccag gggaagggaaattgtggtgc ttctgaaccc 250 atggtcaatt aacgaggcag tttctagcta ctgcacgtacttcataaagc 300 aggactctaa aagctttgga atcatggtgt catggaaagg gatttacttt350 atactgactc tgttttgggg aagctttttt ggaagcattt tcatgctgag 400tcccttttta cctttgatgt ttgtaaaccc atcttggtat cgctggatca 450 acaaccgccttgtggcaaca tggctcaccc tacctgtggc attattggag 500 accatgtttg gtgtaaaagtgattataact ggggatgcat ttgttcctgg 550 agaaagaagt gtcattatca tgaaccatcggacaagaatg gactggatgt 600 tcctgtggaa ttgcctgatg cgatatagct acctcagattggagaaaatt 650 tgcctcaaag cgagtctcaa aggtgttcct ggatttggtt gggccatgca700 ggctgctgcc tatatcttca ttcataggaa atggaaggat gacaagagcc 750atttcgaaga catgattgat tacttttgtg atattcacga accacttcaa 800 ctcctcatattcccagaagg gactgatctc acagaaaaca gcaagtctcg 850 aagtaatgca tttgctgaaaaaaatggact tcagaaatat gaatatgttt 900 tacatccaag aactacaggc tttacttttgtggtagaccg tctaagagaa 950 ggtaagaacc ttgatgctgt ccatgatatc actgtggcgtatcctcacaa 1000 cattcctcaa tcagagaagc acctcctcca aggagacttt cccagggaaa1050 tccactttca cgtccaccgg tatccaatag acaccctccc cacatccaag 1100gaggaccttc aactctggtg ccacaaacgg tgggaagaga aagaagagag 1150 gctgcgttccttctatcaag gggagaagaa tttttatttt accggacaga 1200 gtgtcattcc accttgcaagtctgaactca gggtccttgt ggtcaaattg 1250 ctctctatac tgtattggac cctgttcagccctgcaatgt gcctactcat 1300 atatttgtac agtcttgtta agtggtattt tataatcaccattgtaatct 1350 ttgtgctgca agagagaata tttggtggac tggagatcat agaacttgca1400 tgttaccgac ttttacacaa acagccacat ttaaattcaa agaaaaatga 1450gtaagattat aaggtttgcc atgtgaaaac ctagagcata ttttggaaat 1500 gttctaaacctttctaagct cagatgcatt tttgcatgac tatgtcgaat 1550 atttcttact gccatcattatttgttaaag atattttgca cttaattttg 1600 tgggaaaaat attgctacaa ttttttttaatctctgaatg taatttcgat 1650 actgtgtaca tagcagggag tgatcggggt gaaataacttgggccagaat 1700 attattaaac aatcatcagg cttttaaa 1728 102 414 PRT HomoSapien 102 Met His Ser Arg Gly Arg Glu Ile Val Val Leu Leu Asn Pro Trp 15 10 15 Ser Ile Asn Glu Ala Val Ser Ser Tyr Cys Thr Tyr Phe Ile Lys 2025 30 Gln Asp Ser Lys Ser Phe Gly Ile Met Val Ser Trp Lys Gly Ile 35 4045 Tyr Phe Ile Leu Thr Leu Phe Trp Gly Ser Phe Phe Gly Ser Ile 50 55 60Phe Met Leu Ser Pro Phe Leu Pro Leu Met Phe Val Asn Pro Ser 65 70 75 TrpTyr Arg Trp Ile Asn Asn Arg Leu Val Ala Thr Trp Leu Thr 80 85 90 Leu ProVal Ala Leu Leu Glu Thr Met Phe Gly Val Lys Val Ile 95 100 105 Ile ThrGly Asp Ala Phe Val Pro Gly Glu Arg Ser Val Ile Ile 110 115 120 Met AsnHis Arg Thr Arg Met Asp Trp Met Phe Leu Trp Asn Cys 125 130 135 Leu MetArg Tyr Ser Tyr Leu Arg Leu Glu Lys Ile Cys Leu Lys 140 145 150 Ala SerLeu Lys Gly Val Pro Gly Phe Gly Trp Ala Met Gln Ala 155 160 165 Ala AlaTyr Ile Phe Ile His Arg Lys Trp Lys Asp Asp Lys Ser 170 175 180 His PheGlu Asp Met Ile Asp Tyr Phe Cys Asp Ile His Glu Pro 185 190 195 Leu GlnLeu Leu Ile Phe Pro Glu Gly Thr Asp Leu Thr Glu Asn 200 205 210 Ser LysSer Arg Ser Asn Ala Phe Ala Glu Lys Asn Gly Leu Gln 215 220 225 Lys TyrGlu Tyr Val Leu His Pro Arg Thr Thr Gly Phe Thr Phe 230 235 240 Val ValAsp Arg Leu Arg Glu Gly Lys Asn Leu Asp Ala Val His 245 250 255 Asp IleThr Val Ala Tyr Pro His Asn Ile Pro Gln Ser Glu Lys 260 265 270 His LeuLeu Gln Gly Asp Phe Pro Arg Glu Ile His Phe His Val 275 280 285 His ArgTyr Pro Ile Asp Thr Leu Pro Thr Ser Lys Glu Asp Leu 290 295 300 Gln LeuTrp Cys His Lys Arg Trp Glu Glu Lys Glu Glu Arg Leu 305 310 315 Arg SerPhe Tyr Gln Gly Glu Lys Asn Phe Tyr Phe Thr Gly Gln 320 325 330 Ser ValIle Pro Pro Cys Lys Ser Glu Leu Arg Val Leu Val Val 335 340 345 Lys LeuLeu Ser Ile Leu Tyr Trp Thr Leu Phe Ser Pro Ala Met 350 355 360 Cys LeuLeu Ile Tyr Leu Tyr Ser Leu Val Lys Trp Tyr Phe Ile 365 370 375 Ile ThrIle Val Ile Phe Val Leu Gln Glu Arg Ile Phe Gly Gly 380 385 390 Leu GluIle Ile Glu Leu Ala Cys Tyr Arg Leu Leu His Lys Gln 395 400 405 Pro HisLeu Asn Ser Lys Lys Asn Glu 410 103 2403 DNA Homo Sapien 103 cggctcgagcggctcgagtg aagagcctct ccacggctcc tgcgcctgag 50 acagctggcc tgacctccaaatcatccatc cacccctgct gtcatctgtt 100 ttcatagtgt gagatcaacc cacaggaatatccatggctt ttgtgctcat 150 tttggttctc agtttctacg agctggtgtc aggacagtggcaagtcactg 200 gaccgggcaa gtttgtccag gccttggtgg gggaggacgc cgtgttctcc250 tgctccctct ttcctgagac cagtgcagag gctatggaag tgcggttctt 300caggaatcag ttccatgctg tggtccacct ctacagagat ggggaagact 350 gggaatctaagcagatgcca cagtatcgag ggagaactga gtttgtgaag 400 gactccattg caggggggcgtgtctctcta aggctaaaaa acatcactcc 450 ctcggacatc ggcctgtatg ggtgctggttcagttcccag atttacgatg 500 aggaggccac ctgggagctg cgggtggcag cactgggctcacttcctctc 550 atttccatcg tgggatatgt tgacggaggt atccagttac tctgcctgtc600 ctcaggctgg ttcccccagc ccacagccaa gtggaaaggt ccacaaggac 650aggatttgtc ttcagactcc agagcaaatg cagatgggta cagcctgtat 700 gatgtggagatctccattat agtccaggaa aatgctggga gcatattgtg 750 ttccatccac cttgctgagcagagtcatga ggtggaatcc aaggtattga 800 taggagagac gtttttccag ccctcaccttggcgcctggc ttctatttta 850 ctcgggttac tctgtggtgc cctgtgtggt gttgtcatggggatgataat 900 tgttttcttc aaatccaaag ggaaaatcca ggcggaactg gactggagaa950 gaaagcacgg acaggcagaa ttgagagacg cccggaaaca cgcagtggag 1000gtgactctgg atccagagac ggctcacccg aagctctgcg tttctgatct 1050 gaaaactgtaacccatagaa aagctcccca ggaggtgcct cactctgaga 1100 agagatttac aaggaagagtgtggtggctt ctcagggttt ccaagcaggg 1150 agacattact gggaggtgga cgtgggacaaaatgtagggt ggtatgtggg 1200 agtgtgtcgg gatgacgtag acagggggaa gaacaatgtgactttgtctc 1250 ccaacaatgg gtattgggtc ctcagactga caacagaaca tttgtatttc1300 acattcaatc cccattttat cagcctcccc cccagcaccc ctcctacacg 1350agtaggggtc ttcctggact atgagggtgg gaccatctcc ttcttcaata 1400 caaatgaccagtcccttatt tataccctgc tgacatgtca gtttgaaggc 1450 ttgttgagac cctatatccagcatgcgatg tatgacgagg aaaaggggac 1500 tcccatattc atatgtccag tgtcctggggatgagacaga gaagaccctg 1550 cttaaagggc cccacaccac agacccagac acagccaagggagagtgctc 1600 ccgacaggtg gccccagctt cctctccgga gcctgcgcac agagagtcac1650 gccccccact ctcctttagg gagctgaggt tcttctgccc tgagccctgc 1700agcagcggca gtcacagctt ccagatgagg ggggattggc ctgaccctgt 1750 gggagtcagaagccatggct gccctgaagt ggggacggaa tagactcaca 1800 ttaggtttag tttgtgaaaactccatccag ctaagcgatc ttgaacaagt 1850 cacaacctcc caggctcctc atttgctagtcacggacagt gattcctgcc 1900 tcacaggtga agattaaaga gacaacgaat gtgaatcatgcttgcaggtt 1950 tgagggcaca gtgtttgcta atgatgtgtt tttatattat acattttccc2000 accataaact ctgtttgctt attccacatt aatttacttt tctctatacc 2050aaatcaccca tggaatagtt attgaacacc tgctttgtga ggctcaaaga 2100 ataaagaggaggtaggattt ttcactgatt ctataagccc agcattacct 2150 gataccaaaa ccaggcaaagaaaacagaag aagaggaagg aaaactacag 2200 gtccatatcc ctcattaaca cagacacaaaaattctaaat aaaattttaa 2250 caaattaaac taaacaatat atttaaagat gatatataactactcagtgt 2300 ggtttgtccc acaaatgcag agttggttta atatttaaat atcaaccagt2350 gtaattcagc acattaataa agtaaaaaag aaaaccataa aaaaaaaaaa 2400 aaa2403 104 466 PRT Homo Sapien 104 Met Ala Phe Val Leu Ile Leu Val Leu SerPhe Tyr Glu Leu Val 1 5 10 15 Ser Gly Gln Trp Gln Val Thr Gly Pro GlyLys Phe Val Gln Ala 20 25 30 Leu Val Gly Glu Asp Ala Val Phe Ser Cys SerLeu Phe Pro Glu 35 40 45 Thr Ser Ala Glu Ala Met Glu Val Arg Phe Phe ArgAsn Gln Phe 50 55 60 His Ala Val Val His Leu Tyr Arg Asp Gly Glu Asp TrpGlu Ser 65 70 75 Lys Gln Met Pro Gln Tyr Arg Gly Arg Thr Glu Phe Val LysAsp 80 85 90 Ser Ile Ala Gly Gly Arg Val Ser Leu Arg Leu Lys Asn Ile Thr95 100 105 Pro Ser Asp Ile Gly Leu Tyr Gly Cys Trp Phe Ser Ser Gln Ile110 115 120 Tyr Asp Glu Glu Ala Thr Trp Glu Leu Arg Val Ala Ala Leu Gly125 130 135 Ser Leu Pro Leu Ile Ser Ile Val Gly Tyr Val Asp Gly Gly Ile140 145 150 Gln Leu Leu Cys Leu Ser Ser Gly Trp Phe Pro Gln Pro Thr Ala155 160 165 Lys Trp Lys Gly Pro Gln Gly Gln Asp Leu Ser Ser Asp Ser Arg170 175 180 Ala Asn Ala Asp Gly Tyr Ser Leu Tyr Asp Val Glu Ile Ser Ile185 190 195 Ile Val Gln Glu Asn Ala Gly Ser Ile Leu Cys Ser Ile His Leu200 205 210 Ala Glu Gln Ser His Glu Val Glu Ser Lys Val Leu Ile Gly Glu215 220 225 Thr Phe Phe Gln Pro Ser Pro Trp Arg Leu Ala Ser Ile Leu Leu230 235 240 Gly Leu Leu Cys Gly Ala Leu Cys Gly Val Val Met Gly Met Ile245 250 255 Ile Val Phe Phe Lys Ser Lys Gly Lys Ile Gln Ala Glu Leu Asp260 265 270 Trp Arg Arg Lys His Gly Gln Ala Glu Leu Arg Asp Ala Arg Lys275 280 285 His Ala Val Glu Val Thr Leu Asp Pro Glu Thr Ala His Pro Lys290 295 300 Leu Cys Val Ser Asp Leu Lys Thr Val Thr His Arg Lys Ala Pro305 310 315 Gln Glu Val Pro His Ser Glu Lys Arg Phe Thr Arg Lys Ser Val320 325 330 Val Ala Ser Gln Gly Phe Gln Ala Gly Arg His Tyr Trp Glu Val335 340 345 Asp Val Gly Gln Asn Val Gly Trp Tyr Val Gly Val Cys Arg Asp350 355 360 Asp Val Asp Arg Gly Lys Asn Asn Val Thr Leu Ser Pro Asn Asn365 370 375 Gly Tyr Trp Val Leu Arg Leu Thr Thr Glu His Leu Tyr Phe Thr380 385 390 Phe Asn Pro His Phe Ile Ser Leu Pro Pro Ser Thr Pro Pro Thr395 400 405 Arg Val Gly Val Phe Leu Asp Tyr Glu Gly Gly Thr Ile Ser Phe410 415 420 Phe Asn Thr Asn Asp Gln Ser Leu Ile Tyr Thr Leu Leu Thr Cys425 430 435 Gln Phe Glu Gly Leu Leu Arg Pro Tyr Ile Gln His Ala Met Tyr440 445 450 Asp Glu Glu Lys Gly Thr Pro Ile Phe Ile Cys Pro Val Ser Trp455 460 465 Gly 105 2103 DNA Homo Sapien 105 ccttcacagg actcttcattgctggttggc aatgatgtat cggccagatg 50 tggtgagggc taggaaaaga gtttgttgggaaccctgggt tatcggcctc 100 gtcatcttca tatccctgat tgtcctggca gtgtgcattggactcactgt 150 tcattatgtg agatataatc aaaagaagac ctacaattac tatagcacat200 tgtcatttac aactgacaaa ctatatgctg agtttggcag agaggcttct 250aacaatttta cagaaatgag ccagagactt gaatcaatgg tgaaaaatgc 300 attttataaatctccattaa gggaagaatt tgtcaagtct caggttatca 350 agttcagtca acagaagcatggagtgttgg ctcatatgct gttgatttgt 400 agatttcact ctactgagga tcctgaaactgtagataaaa ttgttcaact 450 tgttttacat gaaaagctgc aagatgctgt aggaccccctaaagtagatc 500 ctcactcagt taaaattaaa aaaatcaaca agacagaaac agacagctat550 ctaaaccatt gctgcggaac acgaagaagt aaaactctag gtcagagtct 600caggatcgtt ggtgggacag aagtagaaga gggtgaatgg ccctggcagg 650 ctagcctgcagtgggatggg agtcatcgct gtggagcaac cttaattaat 700 gccacatggc ttgtgagtgctgctcactgt tttacaacat ataagaaccc 750 tgccagatgg actgcttcct ttggagtaacaataaaacct tcgaaaatga 800 aacggggtct ccggagaata attgtccatg aaaaatacaaacacccatca 850 catgactatg atatttctct tgcagagctt tctagccctg ttccctacac900 aaatgcagta catagagttt gtctccctga tgcatcctat gagtttcaac 950caggtgatgt gatgtttgtg acaggatttg gagcactgaa aaatgatggt 1000 tacagtcaaaatcatcttcg acaagcacag gtgactctca tagacgctac 1050 aacttgcaat gaacctcaagcttacaatga cgccataact cctagaatgt 1100 tatgtgctgg ctccttagaa ggaaaaacagatgcatgcca gggtgactct 1150 ggaggaccac tggttagttc agatgctaga gatatctggtaccttgctgg 1200 aatagtgagc tggggagatg aatgtgcgaa acccaacaag cctggtgttt1250 atactagagt tacggccttg cgggactgga ttacttcaaa aactggtatc 1300taagagacaa aagcctcatg gaacagataa catttttttt tgttttttgg 1350 gtgtggaggccatttttaga gatacagaat tggagaagac ttgcaaaaca 1400 gctagatttg actgatctcaataaactgtt tgcttgatgc atgtattttc 1450 ttcccagctc tgttccgcac gtaagcatcctgcttctgcc agatcaactc 1500 tgtcatctgt gagcaatagt tgaaacttta tgtacatagagaaatagata 1550 atacaatatt acattacagc ctgtattcat ttgttctcta gaagttttgt1600 cagaattttg acttgttgac ataaatttgt aatgcatata tacaatttga 1650agcactcctt ttcttcagtt cctcagctcc tctcatttca gcaaatatcc 1700 attttcaaggtgcagaacaa ggagtgaaag aaaatataag aagaaaaaaa 1750 tcccctacat tttattggcacagaaaagta ttaggtgttt ttcttagtgg 1800 aatattagaa atgatcatat tcattatgaaaggtcaagca aagacagcag 1850 aataccaatc acttcatcat ttaggaagta tgggaactaagttaaggaag 1900 tccagaaaga agccaagata tatccttatt ttcatttcca aacaactact1950 atgataaatg tgaagaagat tctgtttttt tgtgacctat aataattata 2000caaacttcat gcaatgtact tgttctaagc aaattaaagc aaatatttat 2050 ttaacattgttactgaggat gtcaacatat aacaataaaa tataaatcac 2100 cca 2103 106 423 PRTHomo Sapien 106 Met Met Tyr Arg Pro Asp Val Val Arg Ala Arg Lys Arg ValCys 1 5 10 15 Trp Glu Pro Trp Val Ile Gly Leu Val Ile Phe Ile Ser LeuIle 20 25 30 Val Leu Ala Val Cys Ile Gly Leu Thr Val His Tyr Val Arg Tyr35 40 45 Asn Gln Lys Lys Thr Tyr Asn Tyr Tyr Ser Thr Leu Ser Phe Thr 5055 60 Thr Asp Lys Leu Tyr Ala Glu Phe Gly Arg Glu Ala Ser Asn Asn 65 7075 Phe Thr Glu Met Ser Gln Arg Leu Glu Ser Met Val Lys Asn Ala 80 85 90Phe Tyr Lys Ser Pro Leu Arg Glu Glu Phe Val Lys Ser Gln Val 95 100 105Ile Lys Phe Ser Gln Gln Lys His Gly Val Leu Ala His Met Leu 110 115 120Leu Ile Cys Arg Phe His Ser Thr Glu Asp Pro Glu Thr Val Asp 125 130 135Lys Ile Val Gln Leu Val Leu His Glu Lys Leu Gln Asp Ala Val 140 145 150Gly Pro Pro Lys Val Asp Pro His Ser Val Lys Ile Lys Lys Ile 155 160 165Asn Lys Thr Glu Thr Asp Ser Tyr Leu Asn His Cys Cys Gly Thr 170 175 180Arg Arg Ser Lys Thr Leu Gly Gln Ser Leu Arg Ile Val Gly Gly 185 190 195Thr Glu Val Glu Glu Gly Glu Trp Pro Trp Gln Ala Ser Leu Gln 200 205 210Trp Asp Gly Ser His Arg Cys Gly Ala Thr Leu Ile Asn Ala Thr 215 220 225Trp Leu Val Ser Ala Ala His Cys Phe Thr Thr Tyr Lys Asn Pro 230 235 240Ala Arg Trp Thr Ala Ser Phe Gly Val Thr Ile Lys Pro Ser Lys 245 250 255Met Lys Arg Gly Leu Arg Arg Ile Ile Val His Glu Lys Tyr Lys 260 265 270His Pro Ser His Asp Tyr Asp Ile Ser Leu Ala Glu Leu Ser Ser 275 280 285Pro Val Pro Tyr Thr Asn Ala Val His Arg Val Cys Leu Pro Asp 290 295 300Ala Ser Tyr Glu Phe Gln Pro Gly Asp Val Met Phe Val Thr Gly 305 310 315Phe Gly Ala Leu Lys Asn Asp Gly Tyr Ser Gln Asn His Leu Arg 320 325 330Gln Ala Gln Val Thr Leu Ile Asp Ala Thr Thr Cys Asn Glu Pro 335 340 345Gln Ala Tyr Asn Asp Ala Ile Thr Pro Arg Met Leu Cys Ala Gly 350 355 360Ser Leu Glu Gly Lys Thr Asp Ala Cys Gln Gly Asp Ser Gly Gly 365 370 375Pro Leu Val Ser Ser Asp Ala Arg Asp Ile Trp Tyr Leu Ala Gly 380 385 390Ile Val Ser Trp Gly Asp Glu Cys Ala Lys Pro Asn Lys Pro Gly 395 400 405Val Tyr Thr Arg Val Thr Ala Leu Arg Asp Trp Ile Thr Ser Lys 410 415 420Thr Gly Ile 107 2397 DNA Homo Sapien 107 agagaaagaa gcgtctccagctgaagccaa tgcagccctc cggctctccg 50 cgaagaagtt ccctgccccg atgagcccccgccgtgcgtc cccgactatc 100 cccaggcggg cgtggggcac cgggcccagc gccgacgatcgctgccgttt 150 tgcccttggg agtaggatgt ggtgaaagga tggggcttct cccttacggg200 gctcacaatg gccagagaag attccgtgaa gtgtctgcgc tgcctgctct 250acgccctcaa tctgctcttt tggttaatgt ccatcagtgt gttggcagtt 300 tctgcttggatgagggacta cctaaataat gttctcactt taactgcaga 350 aacgagggta gaggaagcagtcattttgac ttactttcct gtggttcatc 400 cggtcatgat tgctgtttgc tgtttccttatcattgtggg gatgttagga 450 tattgtggaa cggtgaaaag aaatctgttg cttcttgcatggtactttgg 500 aagtttgctt gtcattttct gtgtagaact ggcttgtggc gtttggacat550 atgaacagga acttatggtt ccagtacaat ggtcagatat ggtcactttg 600aaagccagga tgacaaatta tggattacct agatatcggt ggcttactca 650 tgcttggaatttttttcaga gagagtttaa gtgctgtgga gtagtatatt 700 tcactgactg gttggaaatgacagagatgg actggccccc agattcctgc 750 tgtgttagag aattcccagg atgttccaaacaggcccacc aggaagatct 800 cagtgacctt tatcaagagg gttgtgggaa gaaaatgtattcctttttga 850 gaggaaccaa acaactgcag gtgctgaggt ttctgggaat ctccattggg900 gtgacacaaa tcctggccat gattctcacc attactctgc tctgggctct 950gtattatgat agaagggagc ctgggacaga ccaaatgatg tccttgaaga 1000 atgacaactctcagcacctg tcatgtccct cagtagaact gttgaaacca 1050 agcctgtcaa gaatctttgaacacacatcc atggcaaaca gctttaatac 1100 acactttgag atggaggagt tataaaaagaaatgtcacag aagaaaacca 1150 caaacttgtt ttattggact tgtgaatttt tgagtacatactatgtgttt 1200 cagaaatatg tagaaataaa aatgttgcca taaaataaca cctaagcata1250 tactattcta tgctttaaaa tgaggatgga aaagtttcat gtcataagtc 1300accacctgga caataattga tgcccttaaa atgctgaaga cagatgtcat 1350 acccactgtgtagcctgtgt atgactttta ctgaacacag ttatgttttg 1400 aggcagcatg gtttgattagcatttccgca tccatgcaaa cgagtcacat 1450 atggtgggac tggagccata gtaaaggttgatttacttct accaactagt 1500 atataaagta ctaattaaat gctaacatag gaagttagaaaatactaata 1550 acttttatta ctcagcgatc tattcttctg atgctaaata aattatatat1600 cagaaaactt tcaatattgg tgactaccta aatgtgattt ttgctggtta 1650ctaaaatatt cttaccactt aaaagagcaa gctaacacat tgtcttaagc 1700 tgatcagggattttttgtat ataagtctgt gttaaatctg tataattcag 1750 tcgatttcag ttctgataatgttaagaata accattatga aaaggaaaat 1800 ttgtcctgta tagcatcatt atttttagcctttcctgtta ataaagcttt 1850 actattctgt cctgggctta tattacacat ataactgttatttaaatact 1900 taaccactaa ttttgaaaat taccagtgtg atacatagga atcattattc1950 agaatgtagt ctggtcttta ggaagtatta ataagaaaat ttgcacataa 2000cttagttgat tcagaaagga cttgtatgct gtttttctcc caaatgaaga 2050 ctctttttgacactaaacac tttttaaaaa gcttatcttt gccttctcca 2100 aacaagaagc aatagtctccaagtcaatat aaattctaca gaaaatagtg 2150 ttctttttct ccagaaaaat gcttgtgagaatcattaaaa catgtgacaa 2200 tttagagatt ctttgtttta tttcactgat taatatactgtggcaaatta 2250 cacagattat taaatttttt tacaagagta tagtatattt atttgaaatg2300 ggaaaagtgc attttactgt attttgtgta ttttgtttat ttctcagaat 2350atggaaagaa aattaaaatg tgtcaataaa tattttctag agagtaa 2397 108 305 PRTHomo Sapien 108 Met Ala Arg Glu Asp Ser Val Lys Cys Leu Arg Cys Leu LeuTyr 1 5 10 15 Ala Leu Asn Leu Leu Phe Trp Leu Met Ser Ile Ser Val LeuAla 20 25 30 Val Ser Ala Trp Met Arg Asp Tyr Leu Asn Asn Val Leu Thr Leu35 40 45 Thr Ala Glu Thr Arg Val Glu Glu Ala Val Ile Leu Thr Tyr Phe 5055 60 Pro Val Val His Pro Val Met Ile Ala Val Cys Cys Phe Leu Ile 65 7075 Ile Val Gly Met Leu Gly Tyr Cys Gly Thr Val Lys Arg Asn Leu 80 85 90Leu Leu Leu Ala Trp Tyr Phe Gly Ser Leu Leu Val Ile Phe Cys 95 100 105Val Glu Leu Ala Cys Gly Val Trp Thr Tyr Glu Gln Glu Leu Met 110 115 120Val Pro Val Gln Trp Ser Asp Met Val Thr Leu Lys Ala Arg Met 125 130 135Thr Asn Tyr Gly Leu Pro Arg Tyr Arg Trp Leu Thr His Ala Trp 140 145 150Asn Phe Phe Gln Arg Glu Phe Lys Cys Cys Gly Val Val Tyr Phe 155 160 165Thr Asp Trp Leu Glu Met Thr Glu Met Asp Trp Pro Pro Asp Ser 170 175 180Cys Cys Val Arg Glu Phe Pro Gly Cys Ser Lys Gln Ala His Gln 185 190 195Glu Asp Leu Ser Asp Leu Tyr Gln Glu Gly Cys Gly Lys Lys Met 200 205 210Tyr Ser Phe Leu Arg Gly Thr Lys Gln Leu Gln Val Leu Arg Phe 215 220 225Leu Gly Ile Ser Ile Gly Val Thr Gln Ile Leu Ala Met Ile Leu 230 235 240Thr Ile Thr Leu Leu Trp Ala Leu Tyr Tyr Asp Arg Arg Glu Pro 245 250 255Gly Thr Asp Gln Met Met Ser Leu Lys Asn Asp Asn Ser Gln His 260 265 270Leu Ser Cys Pro Ser Val Glu Leu Leu Lys Pro Ser Leu Ser Arg 275 280 285Ile Phe Glu His Thr Ser Met Ala Asn Ser Phe Asn Thr His Phe 290 295 300Glu Met Glu Glu Leu 305 109 2339 DNA Homo Sapien 109 ccaaggccagagctgtggac accttatccc actcatcctc atcctcttcc 50 tctgataaag cccctaccagtgctgataaa gtctttctcg tgagagccta 100 gaggccttaa aaaaaaaagt gcttgaaagagaaggggaca aaggaacacc 150 agtattaaga ggattttcca gtgtttctgg cagttggtccagaaggatgc 200 ctccattcct gcttctcacc tgcctcttca tcacaggcac ctccgtgtca250 cccgtggccc tagatccttg ttctgcttac atcagcctga atgagccctg 300gaggaacact gaccaccagt tggatgagtc tcaaggtcct cctctatgtg 350 acaaccatgtgaatggggag tggtaccact tcacgggcat ggcgggagat 400 gccatgccta ccttctgcataccagaaaac cactgtggaa cccacgcacc 450 tgtctggctc aatggcagcc accccctagaaggcgacggc attgtgcaac 500 gccaggcttg tgccagcttc aatgggaact gctgtctctggaacaccacg 550 gtggaagtca aggcttgccc tggaggctac tatgtgtatc gtctgaccaa600 gcccagcgtc tgcttccacg tctactgtgg tcatttttat gacatctgcg 650acgaggactg ccatggcagc tgctcagata ccagcgagtg cacatgcgct 700 ccaggaactgtgctaggccc tgacaggcag acatgctttg atgaaaatga 750 atgtgagcaa aacaacggtggctgcagtga gatctgtgtg aacctcaaaa 800 actcctaccg ctgtgagtgt ggggttggccgtgtgctaag aagtgatggc 850 aagacttgtg aagacgttga aggatgccac aataacaatggtggctgcag 900 ccactcttgc cttggatctg agaaaggcta ccagtgtgaa tgtccccggg950 gcctggtgct gtctgaggat aaccacactt gccaagtccc tgtgttgtgc 1000aaatcaaatg ccattgaagt gaacatcccc agggagctgg ttggtggcct 1050 ggagctcttcctgaccaaca cctcctgccg aggagtgtcc aacggcaccc 1100 atgtcaacat cctcttctctctcaagacat gtggtacagt ggtcgatgtg 1150 gtgaatgaca agattgtggc cagcaacctcgtgacaggtc tacccaagca 1200 gaccccgggg agcagcgggg acttcatcat ccgaaccagcaagctgctga 1250 tcccggtgac ctgcgagttt ccacgcctgt acaccatttc tgaaggatac1300 gttcccaacc ttcgaaactc cccactggaa atcatgagcc gaaatcatgg 1350gatcttccca ttcactctgg agatcttcaa ggacaatgag tttgaagagc 1400 cttaccgggaagctctgccc accctcaagc ttcgtgactc cctctacttt 1450 ggcattgagc ccgtggtgcacgtgagcggc ttggaaagct tggtggagag 1500 ctgctttgcc acccccacct ccaagatcgacgaggtcctg aaatactacc 1550 tcatccggga tggctgtgtt tcagatgact cggtaaagcagtacacatcc 1600 cgggatcacc tagcaaagca cttccaggtc cctgtcttca agtttgtggg1650 caaagaccac aaggaagtgt ttctgcactg ccgggttctt gtctgtggag 1700tgttggacga gcgttcccgc tgtgcccagg gttgccaccg gcgaatgcgt 1750 cgtggggcaggaggagagga ctcagccggt ctacagggcc agacgctaac 1800 aggcggcccg atccgcatcgactgggagga ctagttcgta gccatacctc 1850 gagtccctgc attggacggc tctgctctttggagcttctc cccccaccgc 1900 cctctaagaa catctgccaa cagctgggtt cagacttcacactgtgagtt 1950 cagactccca gcaccaactc actctgattc tggtccattc agtgggcaca2000 ggtcacagca ctgctgaaca atgtggcctg ggtggggttt catctttcta 2050gggttgaaaa ctaaactgtc cacccagaaa gacactcacc ccatttccct 2100 catttctttcctacacttaa atacctcgtg tatggtgcaa tcagaccaca 2150 aaatcagaag ctgggtataatatttcaagt tacaaaccct agaaaaatta 2200 aacagttact gaaattatga cttaaatacccaatgactcc ttaaatatgt 2250 aaattatagt tataccttga aatttcaatt caaatgcagactaattatag 2300 ggaatttgga agtgtatcaa taaaacagta tataatttt 2339 110 545PRT Homo Sapien 110 Met Pro Pro Phe Leu Leu Leu Thr Cys Leu Phe Ile ThrGly Thr 1 5 10 15 Ser Val Ser Pro Val Ala Leu Asp Pro Cys Ser Ala TyrIle Ser 20 25 30 Leu Asn Glu Pro Trp Arg Asn Thr Asp His Gln Leu Asp GluSer 35 40 45 Gln Gly Pro Pro Leu Cys Asp Asn His Val Asn Gly Glu Trp Tyr50 55 60 His Phe Thr Gly Met Ala Gly Asp Ala Met Pro Thr Phe Cys Ile 6570 75 Pro Glu Asn His Cys Gly Thr His Ala Pro Val Trp Leu Asn Gly 80 8590 Ser His Pro Leu Glu Gly Asp Gly Ile Val Gln Arg Gln Ala Cys 95 100105 Ala Ser Phe Asn Gly Asn Cys Cys Leu Trp Asn Thr Thr Val Glu 110 115120 Val Lys Ala Cys Pro Gly Gly Tyr Tyr Val Tyr Arg Leu Thr Lys 125 130135 Pro Ser Val Cys Phe His Val Tyr Cys Gly His Phe Tyr Asp Ile 140 145150 Cys Asp Glu Asp Cys His Gly Ser Cys Ser Asp Thr Ser Glu Cys 155 160165 Thr Cys Ala Pro Gly Thr Val Leu Gly Pro Asp Arg Gln Thr Cys 170 175180 Phe Asp Glu Asn Glu Cys Glu Gln Asn Asn Gly Gly Cys Ser Glu 185 190195 Ile Cys Val Asn Leu Lys Asn Ser Tyr Arg Cys Glu Cys Gly Val 200 205210 Gly Arg Val Leu Arg Ser Asp Gly Lys Thr Cys Glu Asp Val Glu 215 220225 Gly Cys His Asn Asn Asn Gly Gly Cys Ser His Ser Cys Leu Gly 230 235240 Ser Glu Lys Gly Tyr Gln Cys Glu Cys Pro Arg Gly Leu Val Leu 245 250255 Ser Glu Asp Asn His Thr Cys Gln Val Pro Val Leu Cys Lys Ser 260 265270 Asn Ala Ile Glu Val Asn Ile Pro Arg Glu Leu Val Gly Gly Leu 275 280285 Glu Leu Phe Leu Thr Asn Thr Ser Cys Arg Gly Val Ser Asn Gly 290 295300 Thr His Val Asn Ile Leu Phe Ser Leu Lys Thr Cys Gly Thr Val 305 310315 Val Asp Val Val Asn Asp Lys Ile Val Ala Ser Asn Leu Val Thr 320 325330 Gly Leu Pro Lys Gln Thr Pro Gly Ser Ser Gly Asp Phe Ile Ile 335 340345 Arg Thr Ser Lys Leu Leu Ile Pro Val Thr Cys Glu Phe Pro Arg 350 355360 Leu Tyr Thr Ile Ser Glu Gly Tyr Val Pro Asn Leu Arg Asn Ser 365 370375 Pro Leu Glu Ile Met Ser Arg Asn His Gly Ile Phe Pro Phe Thr 380 385390 Leu Glu Ile Phe Lys Asp Asn Glu Phe Glu Glu Pro Tyr Arg Glu 395 400405 Ala Leu Pro Thr Leu Lys Leu Arg Asp Ser Leu Tyr Phe Gly Ile 410 415420 Glu Pro Val Val His Val Ser Gly Leu Glu Ser Leu Val Glu Ser 425 430435 Cys Phe Ala Thr Pro Thr Ser Lys Ile Asp Glu Val Leu Lys Tyr 440 445450 Tyr Leu Ile Arg Asp Gly Cys Val Ser Asp Asp Ser Val Lys Gln 455 460465 Tyr Thr Ser Arg Asp His Leu Ala Lys His Phe Gln Val Pro Val 470 475480 Phe Lys Phe Val Gly Lys Asp His Lys Glu Val Phe Leu His Cys 485 490495 Arg Val Leu Val Cys Gly Val Leu Asp Glu Arg Ser Arg Cys Ala 500 505510 Gln Gly Cys His Arg Arg Met Arg Arg Gly Ala Gly Gly Glu Asp 515 520525 Ser Ala Gly Leu Gln Gly Gln Thr Leu Thr Gly Gly Pro Ile Arg 530 535540 Ile Asp Trp Glu Asp 545 111 2063 DNA Homo Sapien 111 gagagaggcagcagcttgct cagcggacaa ggatgctggg cgtgagggac 50 caaggcctgc cctgcactcgggcctcctcc agccagtgct gaccagggac 100 ttctgacctg ctggccagcc aggacctgtgtggggaggcc ctcctgctgc 150 cttggggtga caatctcagc tccaggctac agggagaccgggaggatcac 200 agagccagca tgttacagga tcctgacagt gatcaacctc tgaacagcct250 cgatgtcaaa cccctgcgca aaccccgtat ccccatggag accttcagaa 300aggtggggat ccccatcatc atagcactac tgagcctggc gagtatcatc 350 attgtggttgtcctcatcaa ggtgattctg gataaatact acttcctctg 400 cgggcagcct ctccacttcatcccgaggaa gcagctgtgt gacggagagc 450 tggactgtcc cttgggggag gacgaggagcactgtgtcaa gagcttcccc 500 gaagggcctg cagtggcagt ccgcctctcc aaggaccgatccacactgca 550 ggtgctggac tcggccacag ggaactggtt ctctgcctgt ttcgacaact600 tcacagaagc tctcgctgag acagcctgta ggcagatggg ctacagcaga 650gctgtggaga ttggcccaga ccaggatctg gatgttgttg aaatcacaga 700 aaacagccaggagcttcgca tgcggaactc aagtgggccc tgtctctcag 750 gctccctggt ctccctgcactgtcttgcct gtgggaagag cctgaagacc 800 ccccgtgtgg tgggtgggga ggaggcctctgtggattctt ggccttggca 850 ggtcagcatc cagtacgaca aacagcacgt ctgtggagggagcatcctgg 900 acccccactg ggtcctcacg gcagcccact gcttcaggaa acataccgat950 gtgttcaact ggaaggtgcg ggcaggctca gacaaactgg gcagcttccc 1000atccctggct gtggccaaga tcatcatcat tgaattcaac cccatgtacc 1050 ccaaagacaatgacatcgcc ctcatgaagc tgcagttccc actcactttc 1100 tcaggcacag tcaggcccatctgtctgccc ttctttgatg aggagctcac 1150 tccagccacc ccactctgga tcattggatggggctttacg aagcagaatg 1200 gagggaagat gtctgacata ctgctgcagg cgtcagtccaggtcattgac 1250 agcacacggt gcaatgcaga cgatgcgtac cagggggaag tcaccgagaa1300 gatgatgtgt gcaggcatcc cggaaggggg tgtggacacc tgccagggtg 1350acagtggtgg gcccctgatg taccaatctg accagtggca tgtggtgggc 1400 atcgttagctggggctatgg ctgcgggggc ccgagcaccc caggagtata 1450 caccaaggtc tcagcctatctcaactggat ctacaatgtc tggaaggctg 1500 agctgtaatg ctgctgcccc tttgcagtgctgggagccgc ttccttcctg 1550 ccctgcccac ctggggatcc cccaaagtca gacacagagcaagagtcccc 1600 ttgggtacac ccctctgccc acagcctcag catttcttgg agcagcaaag1650 ggcctcaatt cctgtaagag accctcgcag cccagaggcg cccagaggaa 1700gtcagcagcc ctagctcggc cacacttggt gctcccagca tcccagggag 1750 agacacagcccactgaacaa ggtctcaggg gtattgctaa gccaagaagg 1800 aactttccca cactactgaatggaagcagg ctgtcttgta aaagcccaga 1850 tcactgtggg ctggagagga gaaggaaagggtctgcgcca gccctgtccg 1900 tcttcaccca tccccaagcc tactagagca agaaaccagttgtaatataa 1950 aatgcactgc cctactgttg gtatgactac cgttacctac tgttgtcatt2000 gttattacag ctatggccac tattattaaa gagctgtgta acatctctgg 2050caaaaaaaaa aaa 2063 112 432 PRT Homo Sapien 112 Met Leu Gln Asp Pro AspSer Asp Gln Pro Leu Asn Ser Leu Asp 1 5 10 15 Val Lys Pro Leu Arg LysPro Arg Ile Pro Met Glu Thr Phe Arg 20 25 30 Lys Val Gly Ile Pro Ile IleIle Ala Leu Leu Ser Leu Ala Ser 35 40 45 Ile Ile Ile Val Val Val Leu IleLys Val Ile Leu Asp Lys Tyr 50 55 60 Tyr Phe Leu Cys Gly Gln Pro Leu HisPhe Ile Pro Arg Lys Gln 65 70 75 Leu Cys Asp Gly Glu Leu Asp Cys Pro LeuGly Glu Asp Glu Glu 80 85 90 His Cys Val Lys Ser Phe Pro Glu Gly Pro AlaVal Ala Val Arg 95 100 105 Leu Ser Lys Asp Arg Ser Thr Leu Gln Val LeuAsp Ser Ala Thr 110 115 120 Gly Asn Trp Phe Ser Ala Cys Phe Asp Asn PheThr Glu Ala Leu 125 130 135 Ala Glu Thr Ala Cys Arg Gln Met Gly Tyr SerArg Ala Val Glu 140 145 150 Ile Gly Pro Asp Gln Asp Leu Asp Val Val GluIle Thr Glu Asn 155 160 165 Ser Gln Glu Leu Arg Met Arg Asn Ser Ser GlyPro Cys Leu Ser 170 175 180 Gly Ser Leu Val Ser Leu His Cys Leu Ala CysGly Lys Ser Leu 185 190 195 Lys Thr Pro Arg Val Val Gly Gly Glu Glu AlaSer Val Asp Ser 200 205 210 Trp Pro Trp Gln Val Ser Ile Gln Tyr Asp LysGln His Val Cys 215 220 225 Gly Gly Ser Ile Leu Asp Pro His Trp Val LeuThr Ala Ala His 230 235 240 Cys Phe Arg Lys His Thr Asp Val Phe Asn TrpLys Val Arg Ala 245 250 255 Gly Ser Asp Lys Leu Gly Ser Phe Pro Ser LeuAla Val Ala Lys 260 265 270 Ile Ile Ile Ile Glu Phe Asn Pro Met Tyr ProLys Asp Asn Asp 275 280 285 Ile Ala Leu Met Lys Leu Gln Phe Pro Leu ThrPhe Ser Gly Thr 290 295 300 Val Arg Pro Ile Cys Leu Pro Phe Phe Asp GluGlu Leu Thr Pro 305 310 315 Ala Thr Pro Leu Trp Ile Ile Gly Trp Gly PheThr Lys Gln Asn 320 325 330 Gly Gly Lys Met Ser Asp Ile Leu Leu Gln AlaSer Val Gln Val 335 340 345 Ile Asp Ser Thr Arg Cys Asn Ala Asp Asp AlaTyr Gln Gly Glu 350 355 360 Val Thr Glu Lys Met Met Cys Ala Gly Ile ProGlu Gly Gly Val 365 370 375 Asp Thr Cys Gln Gly Asp Ser Gly Gly Pro LeuMet Tyr Gln Ser 380 385 390 Asp Gln Trp His Val Val Gly Ile Val Ser TrpGly Tyr Gly Cys 395 400 405 Gly Gly Pro Ser Thr Pro Gly Val Tyr Thr LysVal Ser Ala Tyr 410 415 420 Leu Asn Trp Ile Tyr Asn Val Trp Lys Ala GluLeu 425 430 113 1768 DNA Homo Sapien 113 ggctggactg gaactcctggtcccaagtga tccacccgcc tcagcctccc 50 aaggtgctgt gattataggt gtaagccaccgtgtctggcc tctgaacaac 100 tttttcagca actaaaaaag ccacaggagt tgaactgctaggattctgac 150 tatgctgtgg tggctagtgc tcctactcct acctacatta aaatctgttt200 tttgttctct tgtaactagc ctttaccttc ctaacacaga ggatctgtca 250ctgtggctct ggcccaaacc tgaccttcac tctggaacga gaacagaggt 300 ttctacccacaccgtcccct cgaagccggg gacagcctca ccttgctggc 350 ctctcgctgg agcagtgccctcaccaactg tctcacgtct ggaggcactg 400 actcgggcag tgcaggtagc tgagcctcttggtagctgcg gctttcaagg 450 tgggccttgc cctggccgta gaagggattg acaagcccgaagatttcata 500 ggcgatggct cccactgccc aggcatcagc cttgctgtag tcaatcactg550 ccctggggcc aggacgggcc gtggacacct gctcagaagc agtgggtgag 600acatcacgct gcccgcccat ctaacctttt catgtcctgc acatcacctg 650 atccatgggctaatctgaac tctgtcccaa ggaacccaga gcttgagtga 700 gctgtggctc agacccagaaggggtctgct tagaccacct ggtttatgtg 750 acaggacttg cattctcctg gaacatgagggaacgccgga ggaaagcaaa 800 gtggcaggga aggaacttgt gccaaattat gggtcagaaaagatggaggt 850 gttgggttat cacaaggcat cgagtctcct gcattcagtg gacatgtggg900 ggaagggctg ccgatggcgc atgacacact cgggactcac ctctggggcc 950atcagacagc cgtttccgcc ccgatccacg taccagctgc tgaagggcaa 1000 ctgcaggccgatgctctcat cagccaggca gcagccaaaa tctgcgatca 1050 ccagccaggg gcagccgtctgggaaggagc aagcaaagtg accatttctc 1100 ctcccctcct tccctctgag aggccctcctatgtccctac taaagccacc 1150 agcaagacat agctgacagg ggctaatggc tcagtgttggcccaggaggt 1200 cagcaaggcc tgagagctga tcagaagggc ctgctgtgcg aacacggaaa1250 tgcctccagt aagcacaggc tgcaaaatcc ccaggcaaag gactgtgtgg 1300ctcaatttaa atcatgttct agtaattgga gctgtcccca agaccaaagg 1350 agctagagcttggttcaaat gatctccaag ggcccttata ccccaggaga 1400 ctttgatttg aatttgaaaccccaaatcca aacctaagaa ccaggtgcat 1450 taagaatcag ttattgccgg gtgtggtggcctgtaatgcc aacattttgg 1500 gaggccgagg cgggtagatc acctgaggtc aggagttcaagaccagcctg 1550 gccaacatgg tgaaacccct gtctctacta aaaatacaaa aaaactagcc1600 aggcatggtg gtgtgtgcct gtatcccagc tactcgggag gctgagacag 1650gagaattact tgaacctggg aggtgaagga ggctgagaca ggagaatcac 1700 ttcagcctgagcaacacagc gagactctgt ctcagaaaaa ataaaaaaag 1750 aattatggtt atttgtaa1768 114 109 PRT Homo Sapien 114 Met Leu Trp Trp Leu Val Leu Leu Leu LeuPro Thr Leu Lys Ser 1 5 10 15 Val Phe Cys Ser Leu Val Thr Ser Leu TyrLeu Pro Asn Thr Glu 20 25 30 Asp Leu Ser Leu Trp Leu Trp Pro Lys Pro AspLeu His Ser Gly 35 40 45 Thr Arg Thr Glu Val Ser Thr His Thr Val Pro SerLys Pro Gly 50 55 60 Thr Ala Ser Pro Cys Trp Pro Leu Ala Gly Ala Val ProSer Pro 65 70 75 Thr Val Ser Arg Leu Glu Ala Leu Thr Arg Ala Val Gln ValAla 80 85 90 Glu Pro Leu Gly Ser Cys Gly Phe Gln Gly Gly Pro Cys Pro Gly95 100 105 Arg Arg Arg Asp 115 1197 DNA Homo Sapien 115 cagcagtggtctctcagtcc tctcaaagca aggaaagagt actgtgtgct 50 gagagaccat ggcaaagaatcctccagaga attgtgaaga ctgtcacatt 100 ctaaatgcag aagcttttaa atccaagaaaatatgtaaat cacttaagat 150 ttgtggactg gtgtttggta tcctggccct aactctaattgtcctgtttt 200 gggggagcaa gcacttctgg ccggaggtac ccaaaaaagc ctatgacatg250 gagcacactt tctacagcaa tggagagaag aagaagattt acatggaaat 300tgatcctgtg accagaactg aaatattcag aagcggaaat ggcactgatg 350 aaacattggaagtgcacgac tttaaaaacg gatacactgg catctacttc 400 gtgggtcttc aaaaatgttttatcaaaact cagattaaag tgattcctga 450 attttctgaa ccagaagagg aaatagatgagaatgaagaa attaccacaa 500 ctttctttga acagtcagtg atttgggtcc cagcagaaaagcctattgaa 550 aaccgagatt ttcttaaaaa ttccaaaatt ctggagattt gtgataacgt600 gaccatgtat tggatcaatc ccactctaat atcagtttct gagttacaag 650actttgagga ggagggagaa gatcttcact ttcctgccaa cgaaaaaaaa 700 gggattgaacaaaatgaaca gtgggtggtc cctcaagtga aagtagagaa 750 gacccgtcac gccagacaagcaagtgagga agaacttcca ataaatgact 800 atactgaaaa tggaatagaa tttgatcccatgctggatga gagaggttat 850 tgttgtattt actgccgtcg aggcaaccgc tattgccgccgcgtctgtga 900 acctttacta ggctactacc catatccata ctgctaccaa ggaggacgag950 tcatctgtcg tgtcatcatg ccttgtaact ggtgggtggc ccgcatgctg 1000gggagggtct aataggaggt ttgagctcaa atgcttaaac tgctggcaac 1050 atataataaatgcatgctat tcaatgaatt tctgcctatg aggcatctgg 1100 cccctggtag ccagctctccagaattactt gtaggtaatt cctctcttca 1150 tgttctaata aacttctaca ttatcaccaaaaaaaaaaaa aaaaaaa 1197 116 317 PRT Homo Sapien 116 Met Ala Lys Asn ProPro Glu Asn Cys Glu Asp Cys His Ile Leu 1 5 10 15 Asn Ala Glu Ala PheLys Ser Lys Lys Ile Cys Lys Ser Leu Lys 20 25 30 Ile Cys Gly Leu Val PheGly Ile Leu Ala Leu Thr Leu Ile Val 35 40 45 Leu Phe Trp Gly Ser Lys HisPhe Trp Pro Glu Val Pro Lys Lys 50 55 60 Ala Tyr Asp Met Glu His Thr PheTyr Ser Asn Gly Glu Lys Lys 65 70 75 Lys Ile Tyr Met Glu Ile Asp Pro ValThr Arg Thr Glu Ile Phe 80 85 90 Arg Ser Gly Asn Gly Thr Asp Glu Thr LeuGlu Val His Asp Phe 95 100 105 Lys Asn Gly Tyr Thr Gly Ile Tyr Phe ValGly Leu Gln Lys Cys 110 115 120 Phe Ile Lys Thr Gln Ile Lys Val Ile ProGlu Phe Ser Glu Pro 125 130 135 Glu Glu Glu Ile Asp Glu Asn Glu Glu IleThr Thr Thr Phe Phe 140 145 150 Glu Gln Ser Val Ile Trp Val Pro Ala GluLys Pro Ile Glu Asn 155 160 165 Arg Asp Phe Leu Lys Asn Ser Lys Ile LeuGlu Ile Cys Asp Asn 170 175 180 Val Thr Met Tyr Trp Ile Asn Pro Thr LeuIle Ser Val Ser Glu 185 190 195 Leu Gln Asp Phe Glu Glu Glu Gly Glu AspLeu His Phe Pro Ala 200 205 210 Asn Glu Lys Lys Gly Ile Glu Gln Asn GluGln Trp Val Val Pro 215 220 225 Gln Val Lys Val Glu Lys Thr Arg His AlaArg Gln Ala Ser Glu 230 235 240 Glu Glu Leu Pro Ile Asn Asp Tyr Thr GluAsn Gly Ile Glu Phe 245 250 255 Asp Pro Met Leu Asp Glu Arg Gly Tyr CysCys Ile Tyr Cys Arg 260 265 270 Arg Gly Asn Arg Tyr Cys Arg Arg Val CysGlu Pro Leu Leu Gly 275 280 285 Tyr Tyr Pro Tyr Pro Tyr Cys Tyr Gln GlyGly Arg Val Ile Cys 290 295 300 Arg Val Ile Met Pro Cys Asn Trp Trp ValAla Arg Met Leu Gly 305 310 315 Arg Val 117 2121 DNA Homo Sapien 117gagctcccct caggagcgcg ttagcttcac accttcggca gcaggagggc 50 ggcagcttctcgcaggcggc agggcgggcg gccaggatca tgtccaccac 100 cacatgccaa gtggtggcgttcctcctgtc catcctgggg ctggccggct 150 gcatcgcggc caccgggatg gacatgtggagcacccagga cctgtacgac 200 aaccccgtca cctccgtgtt ccagtacgaa gggctctggaggagctgcgt 250 gaggcagagt tcaggcttca ccgaatgcag gccctatttc accatcctgg300 gacttccagc catgctgcag gcagtgcgag ccctgatgat cgtaggcatc 350gtcctgggtg ccattggcct cctggtatcc atctttgccc tgaaatgcat 400 ccgcattggcagcatggagg actctgccaa agccaacatg acactgacct 450 ccgggatcat gttcattgtctcaggtcttt gtgcaattgc tggagtgtct 500 gtgtttgcca acatgctggt gactaacttctggatgtcca cagctaacat 550 gtacaccggc atgggtggga tggtgcagac tgttcagaccaggtacacat 600 ttggtgcggc tctgttcgtg ggctgggtcg ctggaggcct cacactaatt650 gggggtgtga tgatgtgcat cgcctgccgg ggcctggcac cagaagaaac 700caactacaaa gccgtttctt atcatgcctc aggccacagt gttgcctaca 750 agcctggaggcttcaaggcc agcactggct ttgggtccaa caccaaaaac 800 aagaagatat acgatggaggtgcccgcaca gaggacgagg tacaatctta 850 tccttccaag cacgactatg tgtaatgctctaagacctct cagcacgggc 900 ggaagaaact cccggagagc tcacccaaaa aacaaggagatcccatctag 950 atttcttctt gcttttgact cacagctgga agttagaaaa gcctcgattt1000 catctttgga gaggccaaat ggtcttagcc tcagtctctg tctctaaata 1050ttccaccata aaacagctga gttatttatg aattagaggc tatagctcac 1100 attttcaatcctctatttct ttttttaaat ataactttct actctgatga 1150 gagaatgtgg ttttaatctctctctcacat tttgatgatt tagacagact 1200 ccccctcttc ctcctagtca ataaacccattgatgatcta tttcccagct 1250 tatccccaag aaaacttttg aaaggaaaga gtagacccaaagatgttatt 1300 ttctgctgtt tgaattttgt ctccccaccc ccaacttggc tagtaataaa1350 cacttactga agaagaagca ataagagaaa gatatttgta atctctccag 1400cccatgatct cggttttctt acactgtgat cttaaaagtt accaaaccaa 1450 agtcattttcagtttgaggc aaccaaacct ttctactgct gttgacatct 1500 tcttattaca gcaacaccattctaggagtt tcctgagctc tccactggag 1550 tcctctttct gtcgcgggtc agaaattgtccctagatgaa tgagaaaatt 1600 atttttttta atttaagtcc taaatatagt taaaataaataatgttttag 1650 taaaatgata cactatctct gtgaaatagc ctcaccccta catgtggata1700 gaaggaaatg aaaaaataat tgctttgaca ttgtctatat ggtactttgt 1750aaagtcatgc ttaagtacaa attccatgaa aagctcacac ctgtaatcct 1800 agcactttgggaggctgagg aggaaggatc acttgagccc agaagttcga 1850 gactagcctg ggcaacatggagaagccctg tctctacaaa atacagagag 1900 aaaaaatcag ccagtcatgg tggcatacacctgtagtccc agcattccgg 1950 gaggctgagg tgggaggatc acttgagccc agggaggttggggctgcagt 2000 gagccatgat cacaccactg cactccagcc aggtgacata gcgagatcct2050 gtctaaaaaa ataaaaaata aataatggaa cacagcaagt cctaggaagt 2100aggttaaaac taattcttta a 2121 118 261 PRT Homo Sapien 118 Met Ser Thr ThrThr Cys Gln Val Val Ala Phe Leu Leu Ser Ile 1 5 10 15 Leu Gly Leu AlaGly Cys Ile Ala Ala Thr Gly Met Asp Met Trp 20 25 30 Ser Thr Gln Asp LeuTyr Asp Asn Pro Val Thr Ser Val Phe Gln 35 40 45 Tyr Glu Gly Leu Trp ArgSer Cys Val Arg Gln Ser Ser Gly Phe 50 55 60 Thr Glu Cys Arg Pro Tyr PheThr Ile Leu Gly Leu Pro Ala Met 65 70 75 Leu Gln Ala Val Arg Ala Leu MetIle Val Gly Ile Val Leu Gly 80 85 90 Ala Ile Gly Leu Leu Val Ser Ile PheAla Leu Lys Cys Ile Arg 95 100 105 Ile Gly Ser Met Glu Asp Ser Ala LysAla Asn Met Thr Leu Thr 110 115 120 Ser Gly Ile Met Phe Ile Val Ser GlyLeu Cys Ala Ile Ala Gly 125 130 135 Val Ser Val Phe Ala Asn Met Leu ValThr Asn Phe Trp Met Ser 140 145 150 Thr Ala Asn Met Tyr Thr Gly Met GlyGly Met Val Gln Thr Val 155 160 165 Gln Thr Arg Tyr Thr Phe Gly Ala AlaLeu Phe Val Gly Trp Val 170 175 180 Ala Gly Gly Leu Thr Leu Ile Gly GlyVal Met Met Cys Ile Ala 185 190 195 Cys Arg Gly Leu Ala Pro Glu Glu ThrAsn Tyr Lys Ala Val Ser 200 205 210 Tyr His Ala Ser Gly His Ser Val AlaTyr Lys Pro Gly Gly Phe 215 220 225 Lys Ala Ser Thr Gly Phe Gly Ser AsnThr Lys Asn Lys Lys Ile 230 235 240 Tyr Asp Gly Gly Ala Arg Thr Glu AspGlu Val Gln Ser Tyr Pro 245 250 255 Ser Lys His Asp Tyr Val 260 119 2010DNA Homo Sapien 119 ggaaaaactg ttctcttctg tggcacagag aaccctgcttcaaagcagaa 50 gtagcagttc cggagtccag ctggctaaaa ctcatcccag aggataatgg 100caacccatgc cttagaaatc gctgggctgt ttcttggtgg tgttggaatg 150 gtgggcacagtggctgtcac tgtcatgcct cagtggagag tgtcggcctt 200 cattgaaaac aacatcgtggtttttgaaaa cttctgggaa ggactgtgga 250 tgaattgcgt gaggcaggct aacatcaggatgcagtgcaa aatctatgat 300 tccctgctgg ctctttctcc ggacctacag gcagccagaggactgatgtg 350 tgctgcttcc gtgatgtcct tcttggcttt catgatggcc atccttggca400 tgaaatgcac caggtgcacg ggggacaatg agaaggtgaa ggctcacatt 450ctgctgacgg ctggaatcat cttcatcatc acgggcatgg tggtgctcat 500 ccctgtgagctgggttgcca atgccatcat cagagatttc tataactcaa 550 tagtgaatgt tgcccaaaaacgtgagcttg gagaagctct ctacttagga 600 tggaccacgg cactggtgct gattgttggaggagctctgt tctgctgcgt 650 tttttgttgc aacgaaaaga gcagtagcta cagatactcgataccttccc 700 atcgcacaac ccaaaaaagt tatcacaccg gaaagaagtc accgagcgtc750 tactccagaa gtcagtatgt gtagttgtgt atgttttttt aactttacta 800taaagccatg caaatgacaa aaatctatat tactttctca aaatggaccc 850 caaagaaactttgatttact gttcttaact gcctaatctt aattacagga 900 actgtgcatc agctatttatgattctataa gctatttcag cagaatgaga 950 tattaaaccc aatgctttga ttgttctagaaagtatagta atttgttttc 1000 taaggtggtt caagcatcta ctctttttat catttacttcaaaatgacat 1050 tgctaaagac tgcattattt tactactgta atttctccac gacatagcat1100 tatgtacata gatgagtgta acatttatat ctcacataga gacatgctta 1150tatggtttta tttaaaatga aatgccagtc cattacactg aataaataga 1200 actcaactattgcttttcag ggaaatcatg gatagggttg aagaaggtta 1250 ctattaattg tttaaaaacagcttagggat taatgtcctc catttataat 1300 gaagattaaa atgaaggctt taatcagcattgtaaaggaa attgaatggc 1350 tttctgatat gctgtttttt agcctaggag ttagaaatcctaacttcttt 1400 atcctcttct cccagaggct ttttttttct tgtgtattaa attaacattt1450 ttaaaacgca gatattttgt caaggggctt tgcattcaaa ctgcttttcc 1500agggctatac tcagaagaaa gataaaagtg tgatctaaga aaaagtgatg 1550 gttttaggaaagtgaaaata tttttgtttt tgtatttgaa gaagaatgat 1600 gcattttgac aagaaatcatatatgtatgg atatatttta ataagtattt 1650 gagtacagac tttgaggttt catcaatataaataaaagag cagaaaaata 1700 tgtcttggtt ttcatttgct taccaaaaaa acaacaacaaaaaaagttgt 1750 cctttgagaa cttcacctgc tcctatgtgg gtacctgagt caaaattgtc1800 atttttgttc tgtgaaaaat aaatttcctt cttgtaccat ttctgtttag 1850ttttactaaa atctgtaaat actgtatttt tctgtttatt ccaaatttga 1900 tgaaactgacaatccaattt gaaagtttgt gtcgacgtct gtctagctta 1950 aatgaatgtg ttctatttgctttatacatt tatattaata aattgtacat 2000 ttttctaatt 2010 120 225 PRT HomoSapien 120 Met Ala Thr His Ala Leu Glu Ile Ala Gly Leu Phe Leu Gly Gly 15 10 15 Val Gly Met Val Gly Thr Val Ala Val Thr Val Met Pro Gln Trp 2025 30 Arg Val Ser Ala Phe Ile Glu Asn Asn Ile Val Val Phe Glu Asn 35 4045 Phe Trp Glu Gly Leu Trp Met Asn Cys Val Arg Gln Ala Asn Ile 50 55 60Arg Met Gln Cys Lys Ile Tyr Asp Ser Leu Leu Ala Leu Ser Pro 65 70 75 AspLeu Gln Ala Ala Arg Gly Leu Met Cys Ala Ala Ser Val Met 80 85 90 Ser PheLeu Ala Phe Met Met Ala Ile Leu Gly Met Lys Cys Thr 95 100 105 Arg CysThr Gly Asp Asn Glu Lys Val Lys Ala His Ile Leu Leu 110 115 120 Thr AlaGly Ile Ile Phe Ile Ile Thr Gly Met Val Val Leu Ile 125 130 135 Pro ValSer Trp Val Ala Asn Ala Ile Ile Arg Asp Phe Tyr Asn 140 145 150 Ser IleVal Asn Val Ala Gln Lys Arg Glu Leu Gly Glu Ala Leu 155 160 165 Tyr LeuGly Trp Thr Thr Ala Leu Val Leu Ile Val Gly Gly Ala 170 175 180 Leu PheCys Cys Val Phe Cys Cys Asn Glu Lys Ser Ser Ser Tyr 185 190 195 Arg TyrSer Ile Pro Ser His Arg Thr Thr Gln Lys Ser Tyr His 200 205 210 Thr GlyLys Lys Ser Pro Ser Val Tyr Ser Arg Ser Gln Tyr Val 215 220 225 121 1257DNA Homo Sapien 121 ggagagaggc gcgcgggtga aaggcgcatt gatgcagcctgcggcggcct 50 cggagcgcgg cggagccaga cgctgaccac gttcctctcc tcggtctcct 100ccgcctccag ctccgcgctg cccggcagcc gggagccatg cgaccccagg 150 gccccgccgcctccccgcag cggctccgcg gcctcctgct gctcctgctg 200 ctgcagctgc ccgcgccgtcgagcgcctct gagatcccca aggggaagca 250 aaaggcgcag ctccggcaga gggaggtggtggacctgtat aatggaatgt 300 gcttacaagg gccagcagga gtgcctggtc gagacgggagccctggggcc 350 aatgttattc cgggtacacc tgggatccca ggtcgggatg gattcaaagg400 agaaaagggg gaatgtctga gggaaagctt tgaggagtcc tggacaccca 450actacaagca gtgttcatgg agttcattga attatggcat agatcttggg 500 aaaattgcggagtgtacatt tacaaagatg cgttcaaata gtgctctaag 550 agttttgttc agtggctcacttcggctaaa atgcagaaat gcatgctgtc 600 agcgttggta tttcacattc aatggagctgaatgttcagg acctcttccc 650 attgaagcta taatttattt ggaccaagga agccctgaaatgaattcaac 700 aattaatatt catcgcactt cttctgtgga aggactttgt gaaggaattg750 gtgctggatt agtggatgtt gctatctggg ttggcacttg ttcagattac 800ccaaaaggag atgcttctac tggatggaat tcagtttctc gcatcattat 850 tgaagaactaccaaaataaa tgctttaatt ttcatttgct acctcttttt 900 ttattatgcc ttggaatggttcacttaaat gacattttaa ataagtttat 950 gtatacatct gaatgaaaag caaagctaaatatgtttaca gaccaaagtg 1000 tgatttcaca ctgtttttaa atctagcatt attcattttgcttcaatcaa 1050 aagtggtttc aatatttttt ttagttggtt agaatacttt cttcatagtc1100 acattctctc aacctataat ttggaatatt gttgtggtct tttgtttttt 1150ctcttagtat agcattttta aaaaaatata aaagctacca atctttgtac 1200 aatttgtaaatgttaagaat tttttttata tctgttaaat aaaaattatt 1250 tccaaca 1257 122 243PRT Homo Sapien 122 Met Arg Pro Gln Gly Pro Ala Ala Ser Pro Gln Arg LeuArg Gly 1 5 10 15 Leu Leu Leu Leu Leu Leu Leu Gln Leu Pro Ala Pro SerSer Ala 20 25 30 Ser Glu Ile Pro Lys Gly Lys Gln Lys Ala Gln Leu Arg GlnArg 35 40 45 Glu Val Val Asp Leu Tyr Asn Gly Met Cys Leu Gln Gly Pro Ala50 55 60 Gly Val Pro Gly Arg Asp Gly Ser Pro Gly Ala Asn Val Ile Pro 6570 75 Gly Thr Pro Gly Ile Pro Gly Arg Asp Gly Phe Lys Gly Glu Lys 80 8590 Gly Glu Cys Leu Arg Glu Ser Phe Glu Glu Ser Trp Thr Pro Asn 95 100105 Tyr Lys Gln Cys Ser Trp Ser Ser Leu Asn Tyr Gly Ile Asp Leu 110 115120 Gly Lys Ile Ala Glu Cys Thr Phe Thr Lys Met Arg Ser Asn Ser 125 130135 Ala Leu Arg Val Leu Phe Ser Gly Ser Leu Arg Leu Lys Cys Arg 140 145150 Asn Ala Cys Cys Gln Arg Trp Tyr Phe Thr Phe Asn Gly Ala Glu 155 160165 Cys Ser Gly Pro Leu Pro Ile Glu Ala Ile Ile Tyr Leu Asp Gln 170 175180 Gly Ser Pro Glu Met Asn Ser Thr Ile Asn Ile His Arg Thr Ser 185 190195 Ser Val Glu Gly Leu Cys Glu Gly Ile Gly Ala Gly Leu Val Asp 200 205210 Val Ala Ile Trp Val Gly Thr Cys Ser Asp Tyr Pro Lys Gly Asp 215 220225 Ala Ser Thr Gly Trp Asn Ser Val Ser Arg Ile Ile Ile Glu Glu 230 235240 Leu Pro Lys 123 2379 DNA Homo Sapien 123 gctgagcgtg tgcgcggtacggggctctcc tgccttctgg gctccaacgc 50 agctctgtgg ctgaactggg tgctcatcacgggaactgct gggctatgga 100 atacagatgt ggcagctcag gtagccccaa attgcctggaagaatacatc 150 atgtttttcg ataagaagaa attgtaggat ccagtttttt ttttaaccgc200 cccctcccca ccccccaaaa aaactgtaaa gatgcaaaaa cgtaatatcc 250atgaagatcc tattacctag gaagattttg atgttttgct gcgaatgcgg 300 tgttgggatttatttgttct tggagtgttc tgcgtggctg gcaaagaata 350 atgttccaaa atcggtccatctcccaaggg gtccaatttt tcttcctggg 400 tgtcagcgag ccctgactca ctacagtgcagctgacaggg gctgtcatgc 450 aactggcccc taagccaaag caaaagacct aaggacgacctttgaacaat 500 acaaaggatg ggtttcaatg taattaggct actgagcgga tcagctgtag550 cactggttat agcccccact gtcttactga caatgctttc ttctgccgaa 600cgaggatgcc ctaagggctg taggtgtgaa ggcaaaatgg tatattgtga 650 atctcagaaattacaggaga taccctcaag tatatctgct ggttgcttag 700 gtttgtccct tcgctataacagccttcaaa aacttaagta taatcaattt 750 aaagggctca accagctcac ctggctataccttgaccata accatatcag 800 caatattgac gaaaatgctt ttaatggaat acgcagactcaaagagctga 850 ttcttagttc caatagaatc tcctattttc ttaacaatac cttcagacct900 gtgacaaatt tacggaactt ggatctgtcc tataatcagc tgcattctct 950gggatctgaa cagtttcggg gcttgcggaa gctgctgagt ttacatttac 1000 ggtctaactccctgagaacc atccctgtgc gaatattcca agactgccgc 1050 aacctggaac ttttggacctgggatataac cggatccgaa gtttagccag 1100 gaatgtcttt gctggcatga tcagactcaaagaacttcac ctggagcaca 1150 atcaattttc caagctcaac ctggcccttt ttccaaggttggtcagcctt 1200 cagaaccttt acttgcagtg gaataaaatc agtgtcatag gacagaccat1250 gtcctggacc tggagctcct tacaaaggct tgatttatca ggcaatgaga 1300tcgaagcttt cagtggaccc agtgttttcc agtgtgtccc gaatctgcag 1350 cgcctcaacctggattccaa caagctcaca tttattggtc aagagatttt 1400 ggattcttgg atatccctcaatgacatcag tcttgctggg aatatatggg 1450 aatgcagcag aaatatttgc tcccttgtaaactggctgaa aagttttaaa 1500 ggtctaaggg agaatacaat tatctgtgcc agtcccaaagagctgcaagg 1550 agtaaatgtg atcgatgcag tgaagaacta cagcatctgt ggcaaaagta1600 ctacagagag gtttgatctg gccagggctc tcccaaagcc gacgtttaag 1650cccaagctcc ccaggccgaa gcatgagagc aaaccccctt tgcccccgac 1700 ggtgggagccacagagcccg gcccagagac cgatgctgac gccgagcaca 1750 tctctttcca taaaatcatcgcgggcagcg tggcgctttt cctgtccgtg 1800 ctcgtcatcc tgctggttat ctacgtgtcatggaagcggt accctgcgag 1850 catgaagcag ctgcagcagc gctccctcat gcgaaggcacaggaaaaaga 1900 aaagacagtc cctaaagcaa atgactccca gcacccagga attttatgta1950 gattataaac ccaccaacac ggagaccagc gagatgctgc tgaatgggac 2000gggaccctgc acctataaca aatcgggctc cagggagtgt gaggtatgaa 2050 ccattgtgataaaaagagct cttaaaagct gggaaataag tggtgcttta 2100 ttgaactctg gtgactatcaagggaacgcg atgccccccc tccccttccc 2150 tctccctctc actttggtgg caagatccttccttgtccgt tttagtgcat 2200 tcataatact ggtcattttc ctctcataca taatcaacccattgaaattt 2250 aaataccaca atcaatgtga agcttgaact ccggtttaat ataataccta2300 ttgtataaga ccctttactg attccattaa tgtcgcattt gttttaagat 2350aaaacttctt tcataggtaa aaaaaaaaa 2379 124 513 PRT Homo Sapien 124 Met GlyPhe Asn Val Ile Arg Leu Leu Ser Gly Ser Ala Val Ala 1 5 10 15 Leu ValIle Ala Pro Thr Val Leu Leu Thr Met Leu Ser Ser Ala 20 25 30 Glu Arg GlyCys Pro Lys Gly Cys Arg Cys Glu Gly Lys Met Val 35 40 45 Tyr Cys Glu SerGln Lys Leu Gln Glu Ile Pro Ser Ser Ile Ser 50 55 60 Ala Gly Cys Leu GlyLeu Ser Leu Arg Tyr Asn Ser Leu Gln Lys 65 70 75 Leu Lys Tyr Asn Gln PheLys Gly Leu Asn Gln Leu Thr Trp Leu 80 85 90 Tyr Leu Asp His Asn His IleSer Asn Ile Asp Glu Asn Ala Phe 95 100 105 Asn Gly Ile Arg Arg Leu LysGlu Leu Ile Leu Ser Ser Asn Arg 110 115 120 Ile Ser Tyr Phe Leu Asn AsnThr Phe Arg Pro Val Thr Asn Leu 125 130 135 Arg Asn Leu Asp Leu Ser TyrAsn Gln Leu His Ser Leu Gly Ser 140 145 150 Glu Gln Phe Arg Gly Leu ArgLys Leu Leu Ser Leu His Leu Arg 155 160 165 Ser Asn Ser Leu Arg Thr IlePro Val Arg Ile Phe Gln Asp Cys 170 175 180 Arg Asn Leu Glu Leu Leu AspLeu Gly Tyr Asn Arg Ile Arg Ser 185 190 195 Leu Ala Arg Asn Val Phe AlaGly Met Ile Arg Leu Lys Glu Leu 200 205 210 His Leu Glu His Asn Gln PheSer Lys Leu Asn Leu Ala Leu Phe 215 220 225 Pro Arg Leu Val Ser Leu GlnAsn Leu Tyr Leu Gln Trp Asn Lys 230 235 240 Ile Ser Val Ile Gly Gln ThrMet Ser Trp Thr Trp Ser Ser Leu 245 250 255 Gln Arg Leu Asp Leu Ser GlyAsn Glu Ile Glu Ala Phe Ser Gly 260 265 270 Pro Ser Val Phe Gln Cys ValPro Asn Leu Gln Arg Leu Asn Leu 275 280 285 Asp Ser Asn Lys Leu Thr PheIle Gly Gln Glu Ile Leu Asp Ser 290 295 300 Trp Ile Ser Leu Asn Asp IleSer Leu Ala Gly Asn Ile Trp Glu 305 310 315 Cys Ser Arg Asn Ile Cys SerLeu Val Asn Trp Leu Lys Ser Phe 320 325 330 Lys Gly Leu Arg Glu Asn ThrIle Ile Cys Ala Ser Pro Lys Glu 335 340 345 Leu Gln Gly Val Asn Val IleAsp Ala Val Lys Asn Tyr Ser Ile 350 355 360 Cys Gly Lys Ser Thr Thr GluArg Phe Asp Leu Ala Arg Ala Leu 365 370 375 Pro Lys Pro Thr Phe Lys ProLys Leu Pro Arg Pro Lys His Glu 380 385 390 Ser Lys Pro Pro Leu Pro ProThr Val Gly Ala Thr Glu Pro Gly 395 400 405 Pro Glu Thr Asp Ala Asp AlaGlu His Ile Ser Phe His Lys Ile 410 415 420 Ile Ala Gly Ser Val Ala LeuPhe Leu Ser Val Leu Val Ile Leu 425 430 435 Leu Val Ile Tyr Val Ser TrpLys Arg Tyr Pro Ala Ser Met Lys 440 445 450 Gln Leu Gln Gln Arg Ser LeuMet Arg Arg His Arg Lys Lys Lys 455 460 465 Arg Gln Ser Leu Lys Gln MetThr Pro Ser Thr Gln Glu Phe Tyr 470 475 480 Val Asp Tyr Lys Pro Thr AsnThr Glu Thr Ser Glu Met Leu Leu 485 490 495 Asn Gly Thr Gly Pro Cys ThrTyr Asn Lys Ser Gly Ser Arg Glu 500 505 510 Cys Glu Val 125 998 DNA HomoSapien 125 ccgttatcgt cttgcgctac tgctgaatgt ccgtcccgga ggaggaggag 50aggcttttgc cgctgaccca gagatggccc cgagcgagca aattcctact 100 gtccggctgcgcggctaccg tggccgagct agcaaccttt cccctggatc 150 tcacaaaaac tcgactccaaatgcaaggag aagcagctct tgctcggttg 200 ggagacggtg caagagaatc tgccccctataggggaatgg tgcgcacagc 250 cctagggatc attgaagagg aaggctttct aaagctttggcaaggagtga 300 cacccgccat ttacagacac gtagtgtatt ctggaggtcg aatggtcaca350 tatgaacatc tccgagaggt tgtgtttggc aaaagtgaag atgagcatta 400tcccctttgg aaatcagtca ttggagggat gatggctggt gttattggcc 450 agtttttagccaatccaact gacctagtga aggttcagat gcaaatggaa 500 ggaaaaagga aactggaaggaaaaccattg cgatttcgtg gtgtacatca 550 tgcatttgca aaaatcttag ctgaaggaggaatacgaggg ctttgggcag 600 gctgggtacc caatatacaa agagcagcac tggtgaatatgggagattta 650 accacttatg atacagtgaa acactacttg gtattgaata caccacttga700 ggacaatatc atgactcacg gtttatcaag tttatgttct ggactggtag 750cttctattct gggaacacca gccgatgtca tcaaaagcag aataatgaat 800 caaccacgagataaacaagg aaggggactt ttgtataaat catcgactga 850 ctgcttgatt caggctgttcaaggtgaagg attcatgagt ctatataaag 900 gctttttacc atcttggctg agaatgaccccttggtcaat ggtgttctgg 950 cttacttatg aaaaaatcag agagatgagt ggagtcagtccattttaa 998 126 323 PRT Homo Sapien 126 Met Ser Val Pro Glu Glu Glu GluArg Leu Leu Pro Leu Thr Gln 1 5 10 15 Arg Trp Pro Arg Ala Ser Lys PheLeu Leu Ser Gly Cys Ala Ala 20 25 30 Thr Val Ala Glu Leu Ala Thr Phe ProLeu Asp Leu Thr Lys Thr 35 40 45 Arg Leu Gln Met Gln Gly Glu Ala Ala LeuAla Arg Leu Gly Asp 50 55 60 Gly Ala Arg Glu Ser Ala Pro Tyr Arg Gly MetVal Arg Thr Ala 65 70 75 Leu Gly Ile Ile Glu Glu Glu Gly Phe Leu Lys LeuTrp Gln Gly 80 85 90 Val Thr Pro Ala Ile Tyr Arg His Val Val Tyr Ser GlyGly Arg 95 100 105 Met Val Thr Tyr Glu His Leu Arg Glu Val Val Phe GlyLys Ser 110 115 120 Glu Asp Glu His Tyr Pro Leu Trp Lys Ser Val Ile GlyGly Met 125 130 135 Met Ala Gly Val Ile Gly Gln Phe Leu Ala Asn Pro ThrAsp Leu 140 145 150 Val Lys Val Gln Met Gln Met Glu Gly Lys Arg Lys LeuGlu Gly 155 160 165 Lys Pro Leu Arg Phe Arg Gly Val His His Ala Phe AlaLys Ile 170 175 180 Leu Ala Glu Gly Gly Ile Arg Gly Leu Trp Ala Gly TrpVal Pro 185 190 195 Asn Ile Gln Arg Ala Ala Leu Val Asn Met Gly Asp LeuThr Thr 200 205 210 Tyr Asp Thr Val Lys His Tyr Leu Val Leu Asn Thr ProLeu Glu 215 220 225 Asp Asn Ile Met Thr His Gly Leu Ser Ser Leu Cys SerGly Leu 230 235 240 Val Ala Ser Ile Leu Gly Thr Pro Ala Asp Val Ile LysSer Arg 245 250 255 Ile Met Asn Gln Pro Arg Asp Lys Gln Gly Arg Gly LeuLeu Tyr 260 265 270 Lys Ser Ser Thr Asp Cys Leu Ile Gln Ala Val Gln GlyGlu Gly 275 280 285 Phe Met Ser Leu Tyr Lys Gly Phe Leu Pro Ser Trp LeuArg Met 290 295 300 Thr Pro Trp Ser Met Val Phe Trp Leu Thr Tyr Glu LysIle Arg 305 310 315 Glu Met Ser Gly Val Ser Pro Phe 320 127 1505 DNAHomo Sapien 127 cgcggatcgg acccaagcag gtcggcggcg gcggcaggag agcggccggg50 cgtcagctcc tcgacccccg tgtcgggcta gtccagcgag gcggacgggc 100 ggcgtgggcccatggccagg cccggcatgg agcggtggcg cgaccggctg 150 gcgctggtga cgggggcctcggggggcatc ggcgcggccg tggcccgggc 200 cctggtccag cagggactga aggtggtgggctgcgcccgc actgtgggca 250 acatcgagga gctggctgct gaatgtaaga gtgcaggctaccccgggact 300 ttgatcccct acagatgtga cctatcaaat gaagaggaca tcctctccat350 gttctcagct atccgttctc agcacagcgg tgtagacatc tgcatcaaca 400atgctggctt ggcccggcct gacaccctgc tctcaggcag caccagtggt 450 tggaaggacatgttcaatgt gaacgtgctg gccctcagca tctgcacacg 500 ggaagcctac cagtccatgaaggagcggaa tgtggacgat gggcacatca 550 ttaacatcaa tagcatgtct ggccaccgagtgttacccct gtctgtgacc 600 cacttctata gtgccaccaa gtatgccgtc actgcgctgacagagggact 650 gaggcaagag cttcgggagg cccagaccca catccgagcc acgtgcatct700 ctccaggtgt ggtggagaca caattcgcct tcaaactcca cgacaaggac 750cctgagaagg cagctgccac ctatgagcaa atgaagtgtc tcaaacccga 800 ggatgtggccgaggctgtta tctacgtcct cagcaccccc gcacacatcc 850 agattggaga catccagatgaggcccacgg agcaggtgac ctagtgactg 900 tgggagctcc tccttccctc cccacccttcatggcttgcc tcctgcctct 950 ggattttagg tgttgatttc tggatcacgg gataccacttcctgtccaca 1000 ccccgaccag gggctagaaa atttgtttga gatttttata tcatcttgtc1050 aaattgcttc agttgtaaat gtgaaaaatg ggctggggaa aggaggtggt 1100gtccctaatt gttttacttg ttaacttgtt cttgtgcccc tgggcacttg 1150 gcctttgtctgctctcagtg tcttcccttt gacatgggaa aggagttgtg 1200 gccaaaatcc ccatcttcttgcacctcaac gtctgtggct cagggctggg 1250 gtggcagagg gaggccttca ccttatatctgtgttgttat ccagggctcc 1300 agacttcctc ctctgcctgc cccactgcac cctctcccccttatctatct 1350 ccttctcggc tccccagccc agtcttggct tcttgtcccc tcctggggtc1400 atccctccac tctgactctg actatggcag cagaacacca gggcctggcc 1450cagtggattt catggtgatc attaaaaaag aaaaatcgca accaaaaaaa 1500 aaaaa 1505128 260 PRT Homo Sapien 128 Met Ala Arg Pro Gly Met Glu Arg Trp Arg AspArg Leu Ala Leu 1 5 10 15 Val Thr Gly Ala Ser Gly Gly Ile Gly Ala AlaVal Ala Arg Ala 20 25 30 Leu Val Gln Gln Gly Leu Lys Val Val Gly Cys AlaArg Thr Val 35 40 45 Gly Asn Ile Glu Glu Leu Ala Ala Glu Cys Lys Ser AlaGly Tyr 50 55 60 Pro Gly Thr Leu Ile Pro Tyr Arg Cys Asp Leu Ser Asn GluGlu 65 70 75 Asp Ile Leu Ser Met Phe Ser Ala Ile Arg Ser Gln His Ser Gly80 85 90 Val Asp Ile Cys Ile Asn Asn Ala Gly Leu Ala Arg Pro Asp Thr 95100 105 Leu Leu Ser Gly Ser Thr Ser Gly Trp Lys Asp Met Phe Asn Val 110115 120 Asn Val Leu Ala Leu Ser Ile Cys Thr Arg Glu Ala Tyr Gln Ser 125130 135 Met Lys Glu Arg Asn Val Asp Asp Gly His Ile Ile Asn Ile Asn 140145 150 Ser Met Ser Gly His Arg Val Leu Pro Leu Ser Val Thr His Phe 155160 165 Tyr Ser Ala Thr Lys Tyr Ala Val Thr Ala Leu Thr Glu Gly Leu 170175 180 Arg Gln Glu Leu Arg Glu Ala Gln Thr His Ile Arg Ala Thr Cys 185190 195 Ile Ser Pro Gly Val Val Glu Thr Gln Phe Ala Phe Lys Leu His 200205 210 Asp Lys Asp Pro Glu Lys Ala Ala Ala Thr Tyr Glu Gln Met Lys 215220 225 Cys Leu Lys Pro Glu Asp Val Ala Glu Ala Val Ile Tyr Val Leu 230235 240 Ser Thr Pro Ala His Ile Gln Ile Gly Asp Ile Gln Met Arg Pro 245250 255 Thr Glu Gln Val Thr 260 129 1177 DNA Homo Sapien 129 aacttctacatgggcctcct gctgctggtg ctcttcctca gcctcctgcc 50 ggtggcctac accatcatgtccctcccacc ctcctttgac tgcgggccgt 100 tcaggtgcag agtctcagtt gcccgggagcacctcccctc ccgaggcagt 150 ctgctcagag ggcctcggcc cagaattcca gttctggtttcatgccagcc 200 tgtaaaaggc catggaactt tgggtgaatc accgatgcca tttaagaggg250 ttttctgcca ggatggaaat gttaggtcgt tctgtgtctg cgctgttcat 300ttcagtagcc accagccacc tgtggccgtt gagtgcttga aatgaggaac 350 tgagaaaattaatttctcat gtatttttct catttattta ttaattttta 400 actgatagtt gtacatatttgggggtacat gtgatatttg gatacatgta 450 tacaatatat aatgatcaaa tcagggtaactgggatatcc atcacatcaa 500 acatttattt tttattcttt ttagacagag tctcactctgtcacccaggc 550 tggagtgcag tggtgccatc tcagcttact gcaacctctg cctgccaggt600 tcaagcgatt ctcatgcctc cacctcccaa gtagctggga ctacaggcat 650gcaccacaat gcccaactaa tttttgtatt tttagtagag acggggtttt 700 gccatgttgcccaggctggc cttgaactcc tggcctcaaa caatccactt 750 gcctcggcct cccaaagtgttatgattaca ggcgtgagcc accgtgcctg 800 gcctaaacat ttatcttttc tttgtgttgggaactttgaa attatacaat 850 gaattattgt taactgtcat ctccctgctg tgctatggaacactgggact 900 tcttccctct atctaactgt atatttgtac cagttaacca accgtacttc950 atccccactc ctctctatcc ttcccaacct ctgatcacct cattctactc 1000tctacctcca tgagatccac ttttttagct cccacatgtg agtaagaaaa 1050 tgcaatatttgtctttctgt gcctggctta tttcacttaa cataatgact 1100 tcctgttcca tccatgttgctgcaaatgac aggatttcgt tcttaatttc 1150 aattaaaata accacacatg gcaaaaa 1177130 111 PRT Homo Sapien 130 Met Gly Leu Leu Leu Leu Val Leu Phe Leu SerLeu Leu Pro Val 1 5 10 15 Ala Tyr Thr Ile Met Ser Leu Pro Pro Ser PheAsp Cys Gly Pro 20 25 30 Phe Arg Cys Arg Val Ser Val Ala Arg Glu His LeuPro Ser Arg 35 40 45 Gly Ser Leu Leu Arg Gly Pro Arg Pro Arg Ile Pro ValLeu Val 50 55 60 Ser Cys Gln Pro Val Lys Gly His Gly Thr Leu Gly Glu SerPro 65 70 75 Met Pro Phe Lys Arg Val Phe Cys Gln Asp Gly Asn Val Arg Ser80 85 90 Phe Cys Val Cys Ala Val His Phe Ser Ser His Gln Pro Pro Val 95100 105 Ala Val Glu Cys Leu Lys 110 131 2061 DNA Homo Sapien 131ttctgaagta acggaagcta ccttgtataa agacctcaac actgctgacc 50 atgatcagcgcagcctggag catcttcctc atcgggacta aaattgggct 100 gttccttcaa gtagcacctctatcagttat ggctaaatcc tgtccatctg 150 tgtgtcgctg cgatgcgggt ttcatttactgtaatgatcg ctttctgaca 200 tccattccaa caggaatacc agaggatgct acaactctctaccttcagaa 250 caaccaaata aataatgctg ggattccttc agatttgaaa aacttgctga300 aagtagaaag aatataccta taccacaaca gtttagatga atttcctacc 350aacctcccaa agtatgtaaa agagttacat ttgcaagaaa ataacataag 400 gactatcacttatgattcac tttcaaaaat tccctatctg gaagaattac 450 atttagatga caactctgtctctgcagtta gcatagaaga gggagcattc 500 cgagacagca actatctccg actgcttttcctgtcccgta atcaccttag 550 cacaattccc tggggtttgc ccaggactat agaagaactacgcttggatg 600 ataatcgcat atccactatt tcatcaccat ctcttcaagg tctcactagt650 ctaaaacgcc tggttctaga tggaaacctg ttgaacaatc atggtttagg 700tgacaaagtt ttcttcaacc tagttaattt gacagagctg tccctggtgc 750 ggaattccctgactgctgca ccagtaaacc ttccaggcac aaacctgagg 800 aagctttatc ttcaagataaccacatcaat cgggtgcccc caaatgcttt 850 ttcttatcta aggcagctct atcgactggatatgtccaat aataacctaa 900 gtaatttacc tcagggtatc tttgatgatt tggacaatataacacaactg 950 attcttcgca acaatccctg gtattgcggg tgcaagatga aatgggtacg1000 tgactggtta caatcactac ctgtgaaggt caacgtgcgt gggctcatgt 1050gccaagcccc agaaaaggtt cgtgggatgg ctattaagga tctcaatgca 1100 gaactgtttgattgtaagga cagtgggatt gtaagcacca ttcagataac 1150 cactgcaata cccaacacagtgtatcctgc ccaaggacag tggccagctc 1200 cagtgaccaa acagccagat attaagaaccccaagctcac taaggatcaa 1250 caaaccacag ggagtccctc aagaaaaaca attacaattactgtgaagtc 1300 tgtcacctct gataccattc atatctcttg gaaacttgct ctacctatga1350 ctgctttgag actcagctgg cttaaactgg gccatagccc ggcatttgga 1400tctataacag aaacaattgt aacaggggaa cgcagtgagt acttggtcac 1450 agccctggagcctgattcac cctataaagt atgcatggtt cccatggaaa 1500 ccagcaacct ctacctatttgatgaaactc ctgtttgtat tgagactgaa 1550 actgcacccc ttcgaatgta caaccctacaaccaccctca atcgagagca 1600 agagaaagaa ccttacaaaa accccaattt acctttggctgccatcattg 1650 gtggggctgt ggccctggtt accattgccc ttcttgcttt agtgtgttgg1700 tatgttcata ggaatggatc gctcttctca aggaactgtg catatagcaa 1750agggaggaga agaaaggatg actatgcaga agctggcact aagaaggaca 1800 actctatcctggaaatcagg gaaacttctt ttcagatgtt accaataagc 1850 aatgaaccca tctcgaaggaggagtttgta atacacacca tatttcctcc 1900 taatggaatg aatctgtaca aaaacaatcacagtgaaagc agtagtaacc 1950 gaagctacag agacagtggt attccagact cagatcactcacactcatga 2000 tgctgaagga ctcacagcag acttgtgttt tgggtttttt aaacctaagg2050 gaggtgatgg t 2061 132 649 PRT Homo Sapien 132 Met Ile Ser Ala AlaTrp Ser Ile Phe Leu Ile Gly Thr Lys Ile 1 5 10 15 Gly Leu Phe Leu GlnVal Ala Pro Leu Ser Val Met Ala Lys Ser 20 25 30 Cys Pro Ser Val Cys ArgCys Asp Ala Gly Phe Ile Tyr Cys Asn 35 40 45 Asp Arg Phe Leu Thr Ser IlePro Thr Gly Ile Pro Glu Asp Ala 50 55 60 Thr Thr Leu Tyr Leu Gln Asn AsnGln Ile Asn Asn Ala Gly Ile 65 70 75 Pro Ser Asp Leu Lys Asn Leu Leu LysVal Glu Arg Ile Tyr Leu 80 85 90 Tyr His Asn Ser Leu Asp Glu Phe Pro ThrAsn Leu Pro Lys Tyr 95 100 105 Val Lys Glu Leu His Leu Gln Glu Asn AsnIle Arg Thr Ile Thr 110 115 120 Tyr Asp Ser Leu Ser Lys Ile Pro Tyr LeuGlu Glu Leu His Leu 125 130 135 Asp Asp Asn Ser Val Ser Ala Val Ser IleGlu Glu Gly Ala Phe 140 145 150 Arg Asp Ser Asn Tyr Leu Arg Leu Leu PheLeu Ser Arg Asn His 155 160 165 Leu Ser Thr Ile Pro Trp Gly Leu Pro ArgThr Ile Glu Glu Leu 170 175 180 Arg Leu Asp Asp Asn Arg Ile Ser Thr IleSer Ser Pro Ser Leu 185 190 195 Gln Gly Leu Thr Ser Leu Lys Arg Leu ValLeu Asp Gly Asn Leu 200 205 210 Leu Asn Asn His Gly Leu Gly Asp Lys ValPhe Phe Asn Leu Val 215 220 225 Asn Leu Thr Glu Leu Ser Leu Val Arg AsnSer Leu Thr Ala Ala 230 235 240 Pro Val Asn Leu Pro Gly Thr Asn Leu ArgLys Leu Tyr Leu Gln 245 250 255 Asp Asn His Ile Asn Arg Val Pro Pro AsnAla Phe Ser Tyr Leu 260 265 270 Arg Gln Leu Tyr Arg Leu Asp Met Ser AsnAsn Asn Leu Ser Asn 275 280 285 Leu Pro Gln Gly Ile Phe Asp Asp Leu AspAsn Ile Thr Gln Leu 290 295 300 Ile Leu Arg Asn Asn Pro Trp Tyr Cys GlyCys Lys Met Lys Trp 305 310 315 Val Arg Asp Trp Leu Gln Ser Leu Pro ValLys Val Asn Val Arg 320 325 330 Gly Leu Met Cys Gln Ala Pro Glu Lys ValArg Gly Met Ala Ile 335 340 345 Lys Asp Leu Asn Ala Glu Leu Phe Asp CysLys Asp Ser Gly Ile 350 355 360 Val Ser Thr Ile Gln Ile Thr Thr Ala IlePro Asn Thr Val Tyr 365 370 375 Pro Ala Gln Gly Gln Trp Pro Ala Pro ValThr Lys Gln Pro Asp 380 385 390 Ile Lys Asn Pro Lys Leu Thr Lys Asp GlnGln Thr Thr Gly Ser 395 400 405 Pro Ser Arg Lys Thr Ile Thr Ile Thr ValLys Ser Val Thr Ser 410 415 420 Asp Thr Ile His Ile Ser Trp Lys Leu AlaLeu Pro Met Thr Ala 425 430 435 Leu Arg Leu Ser Trp Leu Lys Leu Gly HisSer Pro Ala Phe Gly 440 445 450 Ser Ile Thr Glu Thr Ile Val Thr Gly GluArg Ser Glu Tyr Leu 455 460 465 Val Thr Ala Leu Glu Pro Asp Ser Pro TyrLys Val Cys Met Val 470 475 480 Pro Met Glu Thr Ser Asn Leu Tyr Leu PheAsp Glu Thr Pro Val 485 490 495 Cys Ile Glu Thr Glu Thr Ala Pro Leu ArgMet Tyr Asn Pro Thr 500 505 510 Thr Thr Leu Asn Arg Glu Gln Glu Lys GluPro Tyr Lys Asn Pro 515 520 525 Asn Leu Pro Leu Ala Ala Ile Ile Gly GlyAla Val Ala Leu Val 530 535 540 Thr Ile Ala Leu Leu Ala Leu Val Cys TrpTyr Val His Arg Asn 545 550 555 Gly Ser Leu Phe Ser Arg Asn Cys Ala TyrSer Lys Gly Arg Arg 560 565 570 Arg Lys Asp Asp Tyr Ala Glu Ala Gly ThrLys Lys Asp Asn Ser 575 580 585 Ile Leu Glu Ile Arg Glu Thr Ser Phe GlnMet Leu Pro Ile Ser 590 595 600 Asn Glu Pro Ile Ser Lys Glu Glu Phe ValIle His Thr Ile Phe 605 610 615 Pro Pro Asn Gly Met Asn Leu Tyr Lys AsnAsn His Ser Glu Ser 620 625 630 Ser Ser Asn Arg Ser Tyr Arg Asp Ser GlyIle Pro Asp Ser Asp 635 640 645 His Ser His Ser 133 1882 DNA Homo Sapien133 ccgtcatccc cctgcagcca cccttcccag agtcctttgc ccaggccacc 50 ccaggcttcttggcagccct gccgggccac ttgtcttcat gtctgccagg 100 gggaggtggg aaggaggtgggaggagggcg tgcagaggca gtctgggctt 150 ggccagagct cagggtgctg agcgtgtgaccagcagtgag cagaggccgg 200 ccatggccag cctggggctg ctgctcctgc tcttactgacagcactgcca 250 ccgctgtggt cctcctcact gcctgggctg gacactgctg aaagtaaagc300 caccattgca gacctgatcc tgtctgcgct ggagagagcc accgtcttcc 350tagaacagag gctgcctgaa atcaacctgg atggcatggt gggggtccga 400 gtgctggaagagcagctaaa aagtgtccgg gagaagtggg cccaggagcc 450 cctgctgcag ccgctgagcctgcgcgtggg gatgctgggg gagaagctgg 500 aggctgccat ccagagatcc ctccactacctcaagctgag tgatcccaag 550 tacctaagag agttccagct gaccctccag cccgggttttggaagctccc 600 acatgcctgg atccacactg atgcctcctt ggtgtacccc acgttcgggc650 cccaggactc attctcagag gagagaagtg acgtgtgcct ggtgcagctg 700ctgggaaccg ggacggacag cagcgagccc tgcggcctct cagacctctg 750 caggagcctcatgaccaagc ccggctgctc aggctactgc ctgtcccacc 800 aactgctctt cttcctctgggccagaatga ggggatgcac acagggacca 850 ctccaacaga gccaggacta tatcaacctcttctgcgcca acatgatgga 900 cttgaaccgc agagctgagg ccatcggata cgcctaccctacccgggaca 950 tcttcatgga aaacatcatg ttctgtggaa tgggcggctt ctccgacttc1000 tacaagctcc ggtggctgga ggccattctc agctggcaga aacagcagga 1050aggatgcttc ggggagcctg atgctgaaga tgaagaatta tctaaagcta 1100 ttcaatatcagcagcatttt tcgaggagag tgaagaggcg agaaaaacaa 1150 tttccagatt ctcgctctgttgctcaggct ggagtacagt ggcgcaatct 1200 cggctcactg caacctttgc ctcctgggttcaagcaattc tcttgcctca 1250 tcctcccgag tagctgggac tacaggagcg tgccaccatacctggctaat 1300 ttttatattt ttttagtaga gacagggttt catcatgttg ctcatgctgg1350 tctcgaactc ctgatctcaa gagatccgcc cacctcaggc tcccaaagtg 1400tgggattata ggtgtgagcc accgtgtctg gctgaaaagc actttcaaag 1450 agactgtgttgaataaaggg ccaaggttct tgccacccag cactcatggg 1500 ggctctctcc cctagatggctgctcctccc acaacacagc cacagcagtg 1550 gcagccctgg gtggcttcct atacatcctggcagaatacc ccccagcaaa 1600 cagagagcca cacccatcca caccgccacc accaagcagccgctgagacg 1650 gacggttcca tgccagctgc ctggaggagg aacagacccc tttagtcctc1700 atcccttaga tcctggaggg cacggatcac atcctgggaa gaaggcatct 1750ggaggataag caaagccacc ccgacaccca atcttggaag ccctgagtag 1800 gcagggccagggtaggtggg ggccgggagg gacccaggtg tgaacggatg 1850 aataaagttc aactgcaactgaaaaaaaaa aa 1882 134 440 PRT Homo Sapien 134 Met Ser Ala Arg Gly ArgTrp Glu Gly Gly Gly Arg Arg Ala Cys 1 5 10 15 Arg Gly Ser Leu Gly LeuAla Arg Ala Gln Gly Ala Glu Arg Val 20 25 30 Thr Ser Ser Glu Gln Arg ProAla Met Ala Ser Leu Gly Leu Leu 35 40 45 Leu Leu Leu Leu Leu Thr Ala LeuPro Pro Leu Trp Ser Ser Ser 50 55 60 Leu Pro Gly Leu Asp Thr Ala Glu SerLys Ala Thr Ile Ala Asp 65 70 75 Leu Ile Leu Ser Ala Leu Glu Arg Ala ThrVal Phe Leu Glu Gln 80 85 90 Arg Leu Pro Glu Ile Asn Leu Asp Gly Met ValGly Val Arg Val 95 100 105 Leu Glu Glu Gln Leu Lys Ser Val Arg Glu LysTrp Ala Gln Glu 110 115 120 Pro Leu Leu Gln Pro Leu Ser Leu Arg Val GlyMet Leu Gly Glu 125 130 135 Lys Leu Glu Ala Ala Ile Gln Arg Ser Leu HisTyr Leu Lys Leu 140 145 150 Ser Asp Pro Lys Tyr Leu Arg Glu Phe Gln LeuThr Leu Gln Pro 155 160 165 Gly Phe Trp Lys Leu Pro His Ala Trp Ile HisThr Asp Ala Ser 170 175 180 Leu Val Tyr Pro Thr Phe Gly Pro Gln Asp SerPhe Ser Glu Glu 185 190 195 Arg Ser Asp Val Cys Leu Val Gln Leu Leu GlyThr Gly Thr Asp 200 205 210 Ser Ser Glu Pro Cys Gly Leu Ser Asp Leu CysArg Ser Leu Met 215 220 225 Thr Lys Pro Gly Cys Ser Gly Tyr Cys Leu SerHis Gln Leu Leu 230 235 240 Phe Phe Leu Trp Ala Arg Met Arg Gly Cys ThrGln Gly Pro Leu 245 250 255 Gln Gln Ser Gln Asp Tyr Ile Asn Leu Phe CysAla Asn Met Met 260 265 270 Asp Leu Asn Arg Arg Ala Glu Ala Ile Gly TyrAla Tyr Pro Thr 275 280 285 Arg Asp Ile Phe Met Glu Asn Ile Met Phe CysGly Met Gly Gly 290 295 300 Phe Ser Asp Phe Tyr Lys Leu Arg Trp Leu GluAla Ile Leu Ser 305 310 315 Trp Gln Lys Gln Gln Glu Gly Cys Phe Gly GluPro Asp Ala Glu 320 325 330 Asp Glu Glu Leu Ser Lys Ala Ile Gln Tyr GlnGln His Phe Ser 335 340 345 Arg Arg Val Lys Arg Arg Glu Lys Gln Phe ProAsp Ser Arg Ser 350 355 360 Val Ala Gln Ala Gly Val Gln Trp Arg Asn LeuGly Ser Leu Gln 365 370 375 Pro Leu Pro Pro Gly Phe Lys Gln Phe Ser CysLeu Ile Leu Pro 380 385 390 Ser Ser Trp Asp Tyr Arg Ser Val Pro Pro TyrLeu Ala Asn Phe 395 400 405 Tyr Ile Phe Leu Val Glu Thr Gly Phe His HisVal Ala His Ala 410 415 420 Gly Leu Glu Leu Leu Ile Ser Arg Asp Pro ProThr Ser Gly Ser 425 430 435 Gln Ser Val Gly Leu 440 135 884 DNA HomoSapien 135 ggtctgagtg cagagctgct gtcatggcgg ccgctctgtg gggcttcttt 50cccgtcctgc tgctgctgct gctatcgggg gatgtccaga gctcggaggt 100 gcccggggctgctgctgagg gatcgggagg gagtggggtc ggcataggag 150 atcgcttcaa gattgaggggcgtgcagttg ttccaggggt gaagcctcag 200 gactggatct cggcggcccg agtgctggtagacggagaag agcacgtcgg 250 tttccttaag acagatggga gttttgtggt tcatgatataccttctggat 300 cttatgtagt ggaagttgta tctccagctt acagatttga tcccgttcga350 gtggatatca cttcgaaagg aaaaatgaga gcaagatatg tgaattacat 400caaaacatca gaggttgtca gactgcccta tcctctccaa atgaaatctt 450 caggtccaccttcttacttt attaaaaggg aatcgtgggg ctggacagac 500 tttctaatga acccaatggttatgatgatg gttcttcctt tattgatatt 550 tgtgcttctg cctaaagtgg tcaacacaagtgatcctgac atgagacggg 600 aaatggagca gtcaatgaat atgctgaatt ccaaccatgagttgcctgat 650 gtttctgagt tcatgacaag actcttctct tcaaaatcat ctggcaaatc700 tagcagcggc agcagtaaaa caggcaaaag tggggctggc aaaaggaggt 750agtcaggccg tccagagctg gcatttgcac aaacacggca acactgggtg 800 gcatccaagtcttggaaaac cgtgtgaagc aactactata aacttgagtc 850 atcccgacgt tgatctcttacaactgtgta tgtt 884 136 242 PRT Homo Sapien 136 Met Ala Ala Ala Leu TrpGly Phe Phe Pro Val Leu Leu Leu Leu 1 5 10 15 Leu Leu Ser Gly Asp ValGln Ser Ser Glu Val Pro Gly Ala Ala 20 25 30 Ala Glu Gly Ser Gly Gly SerGly Val Gly Ile Gly Asp Arg Phe 35 40 45 Lys Ile Glu Gly Arg Ala Val ValPro Gly Val Lys Pro Gln Asp 50 55 60 Trp Ile Ser Ala Ala Arg Val Leu ValAsp Gly Glu Glu His Val 65 70 75 Gly Phe Leu Lys Thr Asp Gly Ser Phe ValVal His Asp Ile Pro 80 85 90 Ser Gly Ser Tyr Val Val Glu Val Val Ser ProAla Tyr Arg Phe 95 100 105 Asp Pro Val Arg Val Asp Ile Thr Ser Lys GlyLys Met Arg Ala 110 115 120 Arg Tyr Val Asn Tyr Ile Lys Thr Ser Glu ValVal Arg Leu Pro 125 130 135 Tyr Pro Leu Gln Met Lys Ser Ser Gly Pro ProSer Tyr Phe Ile 140 145 150 Lys Arg Glu Ser Trp Gly Trp Thr Asp Phe LeuMet Asn Pro Met 155 160 165 Val Met Met Met Val Leu Pro Leu Leu Ile PheVal Leu Leu Pro 170 175 180 Lys Val Val Asn Thr Ser Asp Pro Asp Met ArgArg Glu Met Glu 185 190 195 Gln Ser Met Asn Met Leu Asn Ser Asn His GluLeu Pro Asp Val 200 205 210 Ser Glu Phe Met Thr Arg Leu Phe Ser Ser LysSer Ser Gly Lys 215 220 225 Ser Ser Ser Gly Ser Ser Lys Thr Gly Lys SerGly Ala Gly Lys 230 235 240 Arg Arg 137 1571 DNA Homo Sapien 137gatggcgcag ccacagcttc tgtgagattc gatttctccc cagttcccct 50 gtgggtctgaggggaccaga agggtgagct acgttggctt tctggaaggg 100 gaggctatat gcgtcaattccccaaaacaa gttttgacat ttcccctgaa 150 atgtcattct ctatctattc actgcaagtgcctgctgttc caggccttac 200 ctgctgggca ctaacggcgg agccaggatg gggacagaataaaggagcca 250 cgacctgtgc caccaactcg cactcagact ctgaactcag acctgaaatc300 ttctcttcac gggaggcttg gcagtttttc ttactcctgt ggtctccaga 350tttcaggcct aagatgaaag cctctagtct tgccttcagc cttctctctg 400 ctgcgttttatctcctatgg actccttcca ctggactgaa gacactcaat 450 ttgggaagct gtgtgatcgccacaaacctt caggaaatac gaaatggatt 500 ttctgagata cggggcagtg tgcaagccaaagatggaaac attgacatca 550 gaatcttaag gaggactgag tctttgcaag acacaaagcctgcgaatcga 600 tgctgcctcc tgcgccattt gctaagactc tatctggaca gggtatttaa650 aaactaccag acccctgacc attatactct ccggaagatc agcagcctcg 700ccaattcctt tcttaccatc aagaaggacc tccggctctc tcatgcccac 750 atgacatgccattgtgggga ggaagcaatg aagaaataca gccagattct 800 gagtcacttt gaaaagctggaacctcaggc agcagttgtg aaggctttgg 850 gggaactaga cattcttctg caatggatggaggagacaga ataggaggaa 900 agtgatgctg ctgctaagaa tattcgaggt caagagctccagtcttcaat 950 acctgcagag gaggcatgac cccaaaccac catctcttta ctgtactagt1000 cttgtgctgg tcacagtgta tcttatttat gcattacttg cttccttgca 1050tgattgtctt tatgcatccc caatcttaat tgagaccata cttgtataag 1100 atttttgtaatatctttctg ctattggata tatttattag ttaatatatt 1150 tatttatttt ttgctatttaatgtatttat ttttttactt ggacatgaaa 1200 ctttaaaaaa attcacagat tatatttataacctgactag agcaggtgat 1250 gtatttttat acagtaaaaa aaaaaaacct tgtaaattctagaagagtgg 1300 ctaggggggt tattcatttg tattcaacta aggacatatt tactcatgct1350 gatgctctgt gagatatttg aaattgaacc aatgactact taggatgggt 1400tgtggaataa gttttgatgt ggaattgcac atctacctta caattactga 1450 ccatccccagtagactcccc agtcccataa ttgtgtatct tccagccagg 1500 aatcctacac ggccagcatgtatttctaca aataaagttt tctttgcata 1550 ccaaaaaaaa aaaaaaaaaa a 1571 138261 PRT Homo Sapien 138 Met Arg Gln Phe Pro Lys Thr Ser Phe Asp Ile SerPro Glu Met 1 5 10 15 Ser Phe Ser Ile Tyr Ser Leu Gln Val Pro Ala ValPro Gly Leu 20 25 30 Thr Cys Trp Ala Leu Thr Ala Glu Pro Gly Trp Gly GlnAsn Lys 35 40 45 Gly Ala Thr Thr Cys Ala Thr Asn Ser His Ser Asp Ser GluLeu 50 55 60 Arg Pro Glu Ile Phe Ser Ser Arg Glu Ala Trp Gln Phe Phe Leu65 70 75 Leu Leu Trp Ser Pro Asp Phe Arg Pro Lys Met Lys Ala Ser Ser 8085 90 Leu Ala Phe Ser Leu Leu Ser Ala Ala Phe Tyr Leu Leu Trp Thr 95 100105 Pro Ser Thr Gly Leu Lys Thr Leu Asn Leu Gly Ser Cys Val Ile 110 115120 Ala Thr Asn Leu Gln Glu Ile Arg Asn Gly Phe Ser Glu Ile Arg 125 130135 Gly Ser Val Gln Ala Lys Asp Gly Asn Ile Asp Ile Arg Ile Leu 140 145150 Arg Arg Thr Glu Ser Leu Gln Asp Thr Lys Pro Ala Asn Arg Cys 155 160165 Cys Leu Leu Arg His Leu Leu Arg Leu Tyr Leu Asp Arg Val Phe 170 175180 Lys Asn Tyr Gln Thr Pro Asp His Tyr Thr Leu Arg Lys Ile Ser 185 190195 Ser Leu Ala Asn Ser Phe Leu Thr Ile Lys Lys Asp Leu Arg Leu 200 205210 Ser His Ala His Met Thr Cys His Cys Gly Glu Glu Ala Met Lys 215 220225 Lys Tyr Ser Gln Ile Leu Ser His Phe Glu Lys Leu Glu Pro Gln 230 235240 Ala Ala Val Val Lys Ala Leu Gly Glu Leu Asp Ile Leu Leu Gln 245 250255 Trp Met Glu Glu Thr Glu 260 139 2395 DNA Homo Sapien 139 cctggagccggaagcgcggc tgcagcaggg cgaggctcca ggtggggtcg 50 gttccgcatc cagcctagcgtgtccacgat gcggctgggc tccgggactt 100 tcgctacctg ttgcgtagcg atcgaggtgctagggatcgc ggtcttcctt 150 cggggattct tcccggctcc cgttcgttcc tctgccagagcggaacacgg 200 agcggagccc ccagcgcccg aaccctcggc tggagccagt tctaactgga250 ccacgctgcc accacctctc ttcagtaaag ttgttattgt tctgatagat 300gccttgagag atgattttgt gtttgggtca aagggtgtga aatttatgcc 350 ctacacaacttaccttgtgg aaaaaggagc atctcacagt tttgtggctg 400 aagcaaagcc acctacagttactatgcctc gaatcaaggc attgatgacg 450 gggagccttc ctggctttgt cgacgtcatcaggaacctca attctcctgc 500 actgctggaa gacagtgtga taagacaagc aaaagcagctggaaaaagaa 550 tagtctttta tggagatgaa acctgggtta aattattccc aaagcatttt600 gtggaatatg atggaacaac ctcatttttc gtgtcagatt acacagaggt 650ggataataat gtcacgaggc atttggataa agtattaaaa agaggagatt 700 gggacatattaatcctccac tacctggggc tggaccacat tggccacatt 750 tcagggccca acagccccctgattgggcag aagctgagcg agatggacag 800 cgtgctgatg aagatccaca cctcactgcagtcgaaggag agagagacgc 850 ctttacccaa tttgctggtt ctttgtggtg accatggcatgtctgaaaca 900 ggaagtcacg gggcctcctc caccgaggag gtgaatacac ctctgatttt950 aatcagttct gcgtttgaaa ggaaacccgg tgatatccga catccaaagc 1000acgtccaata gacggatgtg gctgcgacac tggcgatagc acttggctta 1050 ccgattccaaaagacagtgt agggagcctc ctattcccag ttgtggaagg 1100 aagaccaatg agagagcagttgagattttt acatttgaat acagtgcagc 1150 ttagtaaact gttgcaagag aatgtgccgtcatatgaaaa agatcctggg 1200 tttgagcagt ttaaaatgtc agaaagattg catgggaactggatcagact 1250 gtacttggag gaaaagcatt cagaagtcct attcaacctg ggctccaagg1300 ttctcaggca gtacctggat gctctgaaga cgctgagctt gtccctgagt 1350gcacaagtgg cccagttctc accctgctcc tgctcagcgt cccacaggca 1400 ctgcacagaaaggctgagct ggaagtccca ctgtcatctc ctgggttttc 1450 tctgctcttt tatttggtgatcctggttct ttcggccgtt cacgtcattg 1500 tgtgcacctc agctgaaagt tcgtgctacttctgtggcct ctcgtggctg 1550 gcggcaggct gcctttcgtt taccagactc tggttgaacacctggtgtgt 1600 gccaagtgct ggcagtgccc tggacagggg gcctcaggga aggacgtgga1650 gcagccttat cccaggcctc tgggtgtccc gacacaggtg ttcacatctg 1700tgctgtcagg tcagatgcct cagttcttgg aaagctaggt tcctgcgact 1750 gttaccaaggtgattgtaaa gagctggcgg tcacagagga acaagccccc 1800 cagctgaggg ggtgtgtgaatcggacagcc tcccagcaga ggtgtgggag 1850 ctgcagctga gggaagaaga gacaatcggcctggacactc aggagggtca 1900 aaaggagact tggtcgcacc actcatcctg ccacccccagaatgcatcct 1950 gcctcatcag gtccagattt ctttccaagg cggacgtttt ctgttggaat2000 tcttagtcct tggcctcgga caccttcatt cgttagctgg ggagtggtgg 2050tgaggcagtg aagaagaggc ggatggtcac actcagatcc acagagccca 2100 ggatcaagggacccactgca gtggcagcag gactgttggg cccccacccc 2150 aaccctgcac agccctcatcccctcttggc ttgagccgtc agaggccctg 2200 tgctgagtgt ctgaccgaga cactcacagctttgtcatca gggcacaggc 2250 ttcctcggag ccaggatgat ctgtgccacg cttgcacctcgggcccatct 2300 gggctcatgc tctctctcct gctattgaat tagtacctag ctgcacacag2350 tatgtagtta ccaaaagaat aaacggcaat aattgagaaa aaaaa 2395 140 310 PRTHomo Sapien 140 Met Arg Leu Gly Ser Gly Thr Phe Ala Thr Cys Cys Val AlaIle 1 5 10 15 Glu Val Leu Gly Ile Ala Val Phe Leu Arg Gly Phe Phe ProAla 20 25 30 Pro Val Arg Ser Ser Ala Arg Ala Glu His Gly Ala Glu Pro Pro35 40 45 Ala Pro Glu Pro Ser Ala Gly Ala Ser Ser Asn Trp Thr Thr Leu 5055 60 Pro Pro Pro Leu Phe Ser Lys Val Val Ile Val Leu Ile Asp Ala 65 7075 Leu Arg Asp Asp Phe Val Phe Gly Ser Lys Gly Val Lys Phe Met 80 85 90Pro Tyr Thr Thr Tyr Leu Val Glu Lys Gly Ala Ser His Ser Phe 95 100 105Val Ala Glu Ala Lys Pro Pro Thr Val Thr Met Pro Arg Ile Lys 110 115 120Ala Leu Met Thr Gly Ser Leu Pro Gly Phe Val Asp Val Ile Arg 125 130 135Asn Leu Asn Ser Pro Ala Leu Leu Glu Asp Ser Val Ile Arg Gln 140 145 150Ala Lys Ala Ala Gly Lys Arg Ile Val Phe Tyr Gly Asp Glu Thr 155 160 165Trp Val Lys Leu Phe Pro Lys His Phe Val Glu Tyr Asp Gly Thr 170 175 180Thr Ser Phe Phe Val Ser Asp Tyr Thr Glu Val Asp Asn Asn Val 185 190 195Thr Arg His Leu Asp Lys Val Leu Lys Arg Gly Asp Trp Asp Ile 200 205 210Leu Ile Leu His Tyr Leu Gly Leu Asp His Ile Gly His Ile Ser 215 220 225Gly Pro Asn Ser Pro Leu Ile Gly Gln Lys Leu Ser Glu Met Asp 230 235 240Ser Val Leu Met Lys Ile His Thr Ser Leu Gln Ser Lys Glu Arg 245 250 255Glu Thr Pro Leu Pro Asn Leu Leu Val Leu Cys Gly Asp His Gly 260 265 270Met Ser Glu Thr Gly Ser His Gly Ala Ser Ser Thr Glu Glu Val 275 280 285Asn Thr Pro Leu Ile Leu Ile Ser Ser Ala Phe Glu Arg Lys Pro 290 295 300Gly Asp Ile Arg His Pro Lys His Val Gln 305 310 141 754 DNA Homo Sapien141 ggcacgaggc aagccttcca ggttatcgtg acgcaccttg aaagtctgag 50 agctactgccctacagaaag ttactagtgc cctaaagctg gcgctggcac 100 tgatgttact gctgctgttggagtacaact tccctataga aaacaactgc 150 cagcacctta agaccactca caccttcagagtgaagaact taaacccgaa 200 gaaattcagc attcatgacc aggatcacaa agtactggtcctggactctg 250 ggaatctcat agcagttcca gataaaaact acatacgccc agagatcttc300 tttgcattag cctcatcctt gagctcagcc tctgcggaga aaggaagtcc 350gattctcctg ggggtctcta aaggggagtt ttgtctctac tgtgacaagg 400 ataaaggacaaagtcatcca tcccttcagc tgaagaagga gaaactgatg 450 aagctggctg cccaaaaggaatcagcacgc cggcccttca tcttttatag 500 ggctcaggtg ggctcctgga acatgctggagtcggcggct caccccggat 550 ggttcatctg cacctcctgc aattgtaatg agcctgttggggtgacagat 600 aaatttgaga acaggaaaca cattgaattt tcatttcaac cagtttgcaa650 agctgaaatg agccccagtg aggtcagcga ttaggaaact gccccattga 700acgccttcct cgctaatttg aactaattgt ataaaaacac caaacctgct 750 cact 754 142193 PRT Homo Sapien 142 Met Leu Leu Leu Leu Leu Glu Tyr Asn Phe Pro IleGlu Asn Asn 1 5 10 15 Cys Gln His Leu Lys Thr Thr His Thr Phe Arg ValLys Asn Leu 20 25 30 Asn Pro Lys Lys Phe Ser Ile His Asp Gln Asp His LysVal Leu 35 40 45 Val Leu Asp Ser Gly Asn Leu Ile Ala Val Pro Asp Lys AsnTyr 50 55 60 Ile Arg Pro Glu Ile Phe Phe Ala Leu Ala Ser Ser Leu Ser Ser65 70 75 Ala Ser Ala Glu Lys Gly Ser Pro Ile Leu Leu Gly Val Ser Lys 8085 90 Gly Glu Phe Cys Leu Tyr Cys Asp Lys Asp Lys Gly Gln Ser His 95 100105 Pro Ser Leu Gln Leu Lys Lys Glu Lys Leu Met Lys Leu Ala Ala 110 115120 Gln Lys Glu Ser Ala Arg Arg Pro Phe Ile Phe Tyr Arg Ala Gln 125 130135 Val Gly Ser Trp Asn Met Leu Glu Ser Ala Ala His Pro Gly Trp 140 145150 Phe Ile Cys Thr Ser Cys Asn Cys Asn Glu Pro Val Gly Val Thr 155 160165 Asp Lys Phe Glu Asn Arg Lys His Ile Glu Phe Ser Phe Gln Pro 170 175180 Val Cys Lys Ala Glu Met Ser Pro Ser Glu Val Ser Asp 185 190 143 961DNA Homo Sapien 143 ctagagagta tagggcagaa ggatggcaga tgagtgactccacatccaga 50 gctgcctccc tttaatccag gatcctgtcc ttcctgtcct gtaggagtgc 100ctgttgccag tgtggggtga gacaagtttg tcccacaggg ctgtctgagc 150 agataagattaagggctggg tctgtgctca attaactcct gtgggcacgg 200 gggctgggaa gagcaaagtcagcggtgcct acagtcagca ccatgctggg 250 cctgccgtgg aagggaggtc tgtcctgggcgctgctgctg cttctcttag 300 gctcccagat cctgctgatc tatgcctggc atttccacgagcaaagggac 350 tgtgatgaac acaatgtcat ggctcgttac ctccctgcca cagtggagtt400 tgctgtccac acattcaacc aacagagcaa ggactactat gcctacagac 450tggggcacat cttgaattcc tggaaggagc aggtggagtc caagactgta 500 ttctcaatggagctactgct ggggagaact aggtgtggga aatttgaaga 550 cgacattgac aactgccatttccaagaaag cacagagctg aacaatactt 600 tcacctgctt cttcaccatc agcaccaggccctggatgac tcagttcagc 650 ctcctgaaca agacctgctt ggagggattc cactgagtgaaacccactca 700 caggcttgtc catgtgctgc tcccacattc cgtggacatc agcactactc750 tcctgaggac tcttcagtgg ctgagcagct ttggacttgt ttgttatcct 800attttgcatg tgtttgagat ctcagatcag tgttttagaa aatccacaca 850 tcttgagcctaatcatgtag tgtagatcat taaacatcag cattttaaga 900 aaaaaaaaaa aaaaaaaaaaaaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 950 aaaaaaaaaa a 961 144 147 PRT HomoSapien 144 Met Leu Gly Leu Pro Trp Lys Gly Gly Leu Ser Trp Ala Leu Leu 15 10 15 Leu Leu Leu Leu Gly Ser Gln Ile Leu Leu Ile Tyr Ala Trp His 2025 30 Phe His Glu Gln Arg Asp Cys Asp Glu His Asn Val Met Ala Arg 35 4045 Tyr Leu Pro Ala Thr Val Glu Phe Ala Val His Thr Phe Asn Gln 50 55 60Gln Ser Lys Asp Tyr Tyr Ala Tyr Arg Leu Gly His Ile Leu Asn 65 70 75 SerTrp Lys Glu Gln Val Glu Ser Lys Thr Val Phe Ser Met Glu 80 85 90 Leu LeuLeu Gly Arg Thr Arg Cys Gly Lys Phe Glu Asp Asp Ile 95 100 105 Asp AsnCys His Phe Gln Glu Ser Thr Glu Leu Asn Asn Thr Phe 110 115 120 Thr CysPhe Phe Thr Ile Ser Thr Arg Pro Trp Met Thr Gln Phe 125 130 135 Ser LeuLeu Asn Lys Thr Cys Leu Glu Gly Phe His 140 145 145 1157 DNA Homo Sapien145 ctgtgcagct cgaggctcca gaggcacact ccagagagag ccaaggttct 50 gacgcgatgaggaagcacct gagctggtgg tggctggcca ctgtctgcat 100 gctgctcttc agccacctctctgcggtcca gacgaggggc atcaagcaca 150 gaatcaagtg gaaccggaag gccctgcccagcactgccca gatcactgag 200 gcccaggtgg ctgagaaccg cccgggagcc ttcatcaagcaaggccgcaa 250 gctcgacatt gacttcggag ccgagggcaa caggtactac gaggccaact300 actggcagtt ccccgatggc atccactaca acggctgctc tgaggctaat 350gtgaccaagg aggcatttgt caccggctgc atcaatgcca cccaggcggc 400 gaaccagggggagttccaga agccagacaa caagctccac cagcaggtgc 450 tctggcggct ggtccaggagctctgctccc tcaagcattg cgagttttgg 500 ttggagaggg gcgcaggact tcgggtcaccatgcaccagc cagtgctcct 550 ctgccttctg gctttgatct ggctcatggt gaaataagcttgccaggagg 600 ctggcagtac agagcgcagc agcgagcaaa tcctggcaag tgacccagct650 cttctccccc aaacccacgc gtgttctgaa ggtgcccagg agcggcgatg 700cactcgcact gcaaatgccg ctcccacgta tgcgccctgg tatgtgcctg 750 cgttctgatagatgggggac tgtggcttct ccgtcactcc attctcagcc 800 cctagcagag cgtctggcacactagattag tagtaaatgc ttgatgagaa 850 gaacacatca ggcactgcgc cacctgcttcacagtacttc ccaacaactc 900 ttagaggtag gtgtattccc gttttacaga taaggaaactgaggcccaga 950 gagctgaagt actgcaccca gcatcaccag ctagaaagtg gcagagccag1000 gattcaaccc tggcttgtct aaccccaggt tttctgctct gtccaattcc 1050agagctgtct ggtgatcact ttatgtctca cagggaccca catccaaaca 1100 tgtatctctaatgaaattgt gaaagctcca tgtttagaaa taaatgaaaa 1150 cacctga 1157 146 176PRT Homo Sapien 146 Met Arg Lys His Leu Ser Trp Trp Trp Leu Ala Thr ValCys Met 1 5 10 15 Leu Leu Phe Ser His Leu Ser Ala Val Gln Thr Arg GlyIle Lys 20 25 30 His Arg Ile Lys Trp Asn Arg Lys Ala Leu Pro Ser Thr AlaGln 35 40 45 Ile Thr Glu Ala Gln Val Ala Glu Asn Arg Pro Gly Ala Phe Ile50 55 60 Lys Gln Gly Arg Lys Leu Asp Ile Asp Phe Gly Ala Glu Gly Asn 6570 75 Arg Tyr Tyr Glu Ala Asn Tyr Trp Gln Phe Pro Asp Gly Ile His 80 8590 Tyr Asn Gly Cys Ser Glu Ala Asn Val Thr Lys Glu Ala Phe Val 95 100105 Thr Gly Cys Ile Asn Ala Thr Gln Ala Ala Asn Gln Gly Glu Phe 110 115120 Gln Lys Pro Asp Asn Lys Leu His Gln Gln Val Leu Trp Arg Leu 125 130135 Val Gln Glu Leu Cys Ser Leu Lys His Cys Glu Phe Trp Leu Glu 140 145150 Arg Gly Ala Gly Leu Arg Val Thr Met His Gln Pro Val Leu Leu 155 160165 Cys Leu Leu Ala Leu Ile Trp Leu Met Val Lys 170 175 147 333 DNA HomoSapien 147 gccttggcct cccaaagggc tgggattata ggcgtgacca ccatgtctgg 50tccagagtct catttcctga tgatttatag actcaaagaa aactcatgtt 100 cagaagctctcttctcttct ggcctcctct ctgtcttctt tccctctttc 150 ttcttatttt aattagtagcatctactcag agtcatgcaa gctggaaatc 200 tttcattttg cttgtcagtg gggtaggtcactgagtctta gtttttattt 250 tttgaaattt caactttcag attcaggggg tacatgtgaaggtttgtttt 300 atgagtatat tgcatgatgc tgaggtttgg ggt 333 148 73 PRT HomoSapien 148 Met Phe Arg Ser Ser Leu Leu Phe Trp Pro Pro Leu Cys Leu Leu 15 10 15 Ser Leu Phe Leu Leu Ile Leu Ile Ser Ser Ile Tyr Ser Glu Ser 2025 30 Cys Lys Leu Glu Ile Phe His Phe Ala Cys Gln Trp Gly Arg Ser 35 4045 Leu Ser Leu Ser Phe Tyr Phe Leu Lys Phe Gln Leu Ser Asp Ser 50 55 60Gly Gly Thr Cys Glu Gly Leu Phe Tyr Glu Tyr Ile Ala 65 70 149 1893 DNAHomo Sapien 149 gtctccgcgt cacaggaact tcagcaccca cagggcggac agcgctcccc50 tctacctgga gacttgactc ccgcgcgccc caaccctgct tatcccttga 100 ccgtcgagtgtcagagatcc tgcagccgcc cagtcccggc ccctctcccg 150 ccccacaccc accctcctggctcttcctgt ttttactcct ccttttcatt 200 cataacaaaa gctacagctc caggagcccagcgccgggct gtgacccaag 250 ccgagcgtgg aagaatgggg ttcctcggga ccggcacttggattctggtg 300 ttagtgctcc cgattcaagc tttccccaaa cctggaggaa gccaagacaa350 atctctacat aatagagaat taagtgcaga aagacctttg aatgaacaga 400ttgctgaagc agaagaagac aagattaaaa aaacatatcc tccagaaaac 450 aagccaggtcagagcaacta ttcttttgtt gataacttga acctgctaaa 500 ggcaataaca gaaaaggaaaaaattgagaa agaaagacaa tctataagaa 550 gctccccact tgataataag ttgaatgtggaagatgttga ttcaaccaag 600 aatcgaaaac tgatcgatga ttatgactct actaagagtggattggatca 650 taaatttcaa gatgatccag atggtcttca tcaactagac gggactcctt700 taaccgctga agacattgtc cataaaatcg ctgccaggat ttatgaagaa 750aatgacagag ccgtgtttga caagattgtt tctaaactac ttaatctcgg 800 ccttatcacagaaagccaag cacatacact ggaagatgaa gtagcagagg 850 ttttacaaaa attaatctcaaaggaagcca acaattatga ggaggatccc 900 aataagccca caagctggac tgagaatcaggctggaaaaa taccagagaa 950 agtgactcca atggcagcaa ttcaagatgg tcttgctaagggagaaaacg 1000 atgaaacagt atctaacaca ttaaccttga caaatggctt ggaaaggaga1050 actaaaacct acagtgaaga caactttgag gaactccaat atttcccaaa 1100tttctatgcg ctactgaaaa gtattgattc agaaaaagaa gcaaaagaga 1150 aagaaacactgattactatc atgaaaacac tgattgactt tgtgaagatg 1200 atggtgaaat atggaacaatatctccagaa gaaggtgttt cctaccttga 1250 aaacttggat gaaatgattg ctcttcagaccaaaaacaag ctagaaaaaa 1300 atgctactga caatataagc aagcttttcc cagcaccatcagagaagagt 1350 catgaagaaa cagacagtac caaggaagaa gcagctaaga tggaaaagga1400 atatggaagc ttgaaggatt ccacaaaaga tgataactcc aacccaggag 1450gaaagacaga tgaacccaaa ggaaaaacag aagcctattt ggaagccatc 1500 agaaaaaatattgaatggtt gaagaaacat gacaaaaagg gaaataaaga 1550 agattatgac ctttcaaagatgagagactt catcaataaa caagctgatg 1600 cttatgtgga gaaaggcatc cttgacaaggaagaagccga ggccatcaag 1650 cgcatttata gcagcctgta aaaatggcaa aagatccaggagtctttcaa 1700 ctgtttcaga aaacataata tagcttaaaa cacttctaat tctgtgatta1750 aaattttttg acccaagggt tattagaaag tgctgaattt acagtagtta 1800accttttaca agtggttaaa acatagcttt cttcccgtaa aaactatctg 1850 aaagtaaagttgtatgtaag ctgaaaaaaa aaaaaaaaaa aaa 1893 150 468 PRT Homo Sapien 150Met Gly Phe Leu Gly Thr Gly Thr Trp Ile Leu Val Leu Val Leu 1 5 10 15Pro Ile Gln Ala Phe Pro Lys Pro Gly Gly Ser Gln Asp Lys Ser 20 25 30 LeuHis Asn Arg Glu Leu Ser Ala Glu Arg Pro Leu Asn Glu Gln 35 40 45 Ile AlaGlu Ala Glu Glu Asp Lys Ile Lys Lys Thr Tyr Pro Pro 50 55 60 Glu Asn LysPro Gly Gln Ser Asn Tyr Ser Phe Val Asp Asn Leu 65 70 75 Asn Leu Leu LysAla Ile Thr Glu Lys Glu Lys Ile Glu Lys Glu 80 85 90 Arg Gln Ser Ile ArgSer Ser Pro Leu Asp Asn Lys Leu Asn Val 95 100 105 Glu Asp Val Asp SerThr Lys Asn Arg Lys Leu Ile Asp Asp Tyr 110 115 120 Asp Ser Thr Lys SerGly Leu Asp His Lys Phe Gln Asp Asp Pro 125 130 135 Asp Gly Leu His GlnLeu Asp Gly Thr Pro Leu Thr Ala Glu Asp 140 145 150 Ile Val His Lys IleAla Ala Arg Ile Tyr Glu Glu Asn Asp Arg 155 160 165 Ala Val Phe Asp LysIle Val Ser Lys Leu Leu Asn Leu Gly Leu 170 175 180 Ile Thr Glu Ser GlnAla His Thr Leu Glu Asp Glu Val Ala Glu 185 190 195 Val Leu Gln Lys LeuIle Ser Lys Glu Ala Asn Asn Tyr Glu Glu 200 205 210 Asp Pro Asn Lys ProThr Ser Trp Thr Glu Asn Gln Ala Gly Lys 215 220 225 Ile Pro Glu Lys ValThr Pro Met Ala Ala Ile Gln Asp Gly Leu 230 235 240 Ala Lys Gly Glu AsnAsp Glu Thr Val Ser Asn Thr Leu Thr Leu 245 250 255 Thr Asn Gly Leu GluArg Arg Thr Lys Thr Tyr Ser Glu Asp Asn 260 265 270 Phe Glu Glu Leu GlnTyr Phe Pro Asn Phe Tyr Ala Leu Leu Lys 275 280 285 Ser Ile Asp Ser GluLys Glu Ala Lys Glu Lys Glu Thr Leu Ile 290 295 300 Thr Ile Met Lys ThrLeu Ile Asp Phe Val Lys Met Met Val Lys 305 310 315 Tyr Gly Thr Ile SerPro Glu Glu Gly Val Ser Tyr Leu Glu Asn 320 325 330 Leu Asp Glu Met IleAla Leu Gln Thr Lys Asn Lys Leu Glu Lys 335 340 345 Asn Ala Thr Asp AsnIle Ser Lys Leu Phe Pro Ala Pro Ser Glu 350 355 360 Lys Ser His Glu GluThr Asp Ser Thr Lys Glu Glu Ala Ala Lys 365 370 375 Met Glu Lys Glu TyrGly Ser Leu Lys Asp Ser Thr Lys Asp Asp 380 385 390 Asn Ser Asn Pro GlyGly Lys Thr Asp Glu Pro Lys Gly Lys Thr 395 400 405 Glu Ala Tyr Leu GluAla Ile Arg Lys Asn Ile Glu Trp Leu Lys 410 415 420 Lys His Asp Lys LysGly Asn Lys Glu Asp Tyr Asp Leu Ser Lys 425 430 435 Met Arg Asp Phe IleAsn Lys Gln Ala Asp Ala Tyr Val Glu Lys 440 445 450 Gly Ile Leu Asp LysGlu Glu Ala Glu Ala Ile Lys Arg Ile Tyr 455 460 465 Ser Ser Leu 151 2598DNA Homo Sapien 151 cggctcgagg ctcccgccag gagaaaggaa cattctgaggggagtctaca 50 ccctgtggag ctcaagatgg tcctgagtgg ggcgctgtgc ttccgaatga 100aggactcggc attgaaggtg ctttatctgc ataataacca gcttctagct 150 ggagggctgcatgcagggaa ggtcattaaa ggtgaagaga tcagcgtggt 200 ccccaatcgg tggctggatgccagcctgtc ccccgtcatc ctgggtgtcc 250 agggtggaag ccagtgcctg tcatgtggggtggggcagga gccgactcta 300 acactagagc cagtgaacat catggagctc tatcttggtgccaaggaatc 350 caagagcttc accttctacc ggcgggacat ggggctcacc tccagcttcg400 agtcggctgc ctacccgggc tggttcctgt gcacggtgcc tgaagccgat 450cagcctgtca gactcaccca gcttcccgag aatggtggct ggaatgcccc 500 catcacagacttctacttcc agcagtgtga ctagggcaac gtgcccccca 550 gaactccctg ggcagagccagctcgggtga ggggtgagtg gaggagaccc 600 atggcggaca atcactctct ctgctctcaggacccccacg tctgacttag 650 tgggcacctg accactttgt cttctggttc ccagtttggataaattctga 700 gatttggagc tcagtccacg gtcctccccc actggatggt gctactgctg750 tggaaccttg taaaaaccat gtggggtaaa ctgggaataa catgaaaaga 800tttctgtggg ggtggggtgg gggagtggtg ggaatcattc ctgcttaatg 850 gtaactgacaagtgttaccc tgagccccgc aggccaaccc atccccagtt 900 gagccttata gggtcagtagctctccacat gaagtcctgt cactcaccac 950 tgtgcaggag agggaggtgg tcatagagtcagggatctat ggcccttggc 1000 ccagccccac ccccttccct ttaatcctgc cactgtcatatgctaccttt 1050 cctatctctt ccctcatcat cttgttgtgg gcatgaggag gtggtgatgt1100 cagaagaaat ggctcgagct cagaagataa aagataagta gggtatgctg 1150atcctctttt aaaaacccaa gatacaatca aaatcccaga tgctggtctc 1200 tattcccatgaaaaagtgct catgacatat tgagaagacc tacttacaaa 1250 gtggcatata ttgcaatttattttaattaa aagataccta tttatatatt 1300 tctttataga aaaaagtctg gaagagtttacttcaattgt agcaatgtca 1350 gggtggtggc agtataggtg atttttcttt taattctgttaatttatctg 1400 tatttcctaa tttttctaca atgaagatga attccttgta taaaaataag1450 aaaagaaatt aatcttgagg taagcagagc agacatcatc tctgattgtc 1500ctcagcctcc acttccccag agtaaattca aattgaatcg agctctgctg 1550 ctctggttggttgtagtagt gatcaggaaa cagatctcag caaagccact 1600 gaggaggagg ctgtgctgagtttgtgtggc tggaatctct gggtaaggaa 1650 cttaaagaac aaaaatcatc tggtaattctttcctagaag gatcacagcc 1700 cctgggattc caaggcattg gatccagtct ctaagaaggctgctgtactg 1750 gttgaattgt gtccccctca aattcacatc cttcttggaa tctcagtctg1800 tgagtttatt tggagataag gtctctgcag atgtagttag ttaagacaag 1850gtcatgctgg atgaaggtag acctaaattc aatatgactg gtttccttgt 1900 atgaaaaggagaggacacag agacagagga gacgcgggga agactatgta 1950 aagatgaagg cagagatcggagttttgcag ccacaagcta agaaacacca 2000 aggattgtgg caaccatcag aagcttggaagaggcaaaga agaattcttc 2050 cctagaggct ttagagggat aacggctctg ctgaaaccttaatctcagac 2100 ttccagcctc ctgaacgaag aaagaataaa tttcggctgt tttaagccac2150 caaggataat tggttacagc agctctagga aactaataca gctgctaaaa 2200tgatccctgt ctcctcgtgt ttacattctg tgtgtgtccc ctcccacaat 2250 gtaccaaagttgtctttgtg accaatagaa tatggcagaa gtgatggcat 2300 gccacttcca agattaggttataaaagaca ctgcagcttc tacttgagcc 2350 ctctctctct gccacccacc gcccccaatctatcttggct cactcgctct 2400 gggggaagct agctgccatg ctatgagcag gcctataaagagacttacgt 2450 ggtaaaaaat gaagtctcct gcccacagcc acattagtga acctagaagc2500 agagactctg tgagataatc gatgtttgtt gttttaagtt gctcagtttt 2550ggtctaactt gttatgcagc aatagataaa taatatgcag agaaagag 2598 152 155 PRTHomo Sapien 152 Met Val Leu Ser Gly Ala Leu Cys Phe Arg Met Lys Asp SerAla 1 5 10 15 Leu Lys Val Leu Tyr Leu His Asn Asn Gln Leu Leu Ala GlyGly 20 25 30 Leu His Ala Gly Lys Val Ile Lys Gly Glu Glu Ile Ser Val Val35 40 45 Pro Asn Arg Trp Leu Asp Ala Ser Leu Ser Pro Val Ile Leu Gly 5055 60 Val Gln Gly Gly Ser Gln Cys Leu Ser Cys Gly Val Gly Gln Glu 65 7075 Pro Thr Leu Thr Leu Glu Pro Val Asn Ile Met Glu Leu Tyr Leu 80 85 90Gly Ala Lys Glu Ser Lys Ser Phe Thr Phe Tyr Arg Arg Asp Met 95 100 105Gly Leu Thr Ser Ser Phe Glu Ser Ala Ala Tyr Pro Gly Trp Phe 110 115 120Leu Cys Thr Val Pro Glu Ala Asp Gln Pro Val Arg Leu Thr Gln 125 130 135Leu Pro Glu Asn Gly Gly Trp Asn Ala Pro Ile Thr Asp Phe Tyr 140 145 150Phe Gln Gln Cys Asp 155 153 1152 DNA Homo Sapien 153 cttcagaacaggttctcctt ccccagtcac cagttgctcg agttagaatt 50 gtctgcaatg gccgccctgcagaaatctgt gagctctttc cttatgggga 100 ccctggccac cagctgcctc cttctcttggccctcttggt acagggagga 150 gcagctgcgc ccatcagctc ccactgcagg cttgacaagtccaacttcca 200 gcagccctat atcaccaacc gcaccttcat gctggctaag gaggctagct250 tggctgataa caacacagac gttcgtctca ttggggagaa actgttccac 300ggagtcagta tgagtgagcg ctgctatctg atgaagcagg tgctgaactt 350 cacccttgaagaagtgctgt tccctcaatc tgataggttc cagccttata 400 tgcaggaggt ggtgcccttcctggccaggc tcagcaacag gctaagcaca 450 tgtcatattg aaggtgatga cctgcatatccagaggaatg tgcaaaagct 500 gaaggacaca gtgaaaaagc ttggagagag tggagagatcaaagcaattg 550 gagaactgga tttgctgttt atgtctctga gaaatgcctg catttgacca600 gagcaaagct gaaaaatgaa taactaaccc cctttccctg ctagaaataa 650caattagatg ccccaaagcg atttttttta accaaaagga agatgggaag 700 ccaaactccatcatgatggg tggattccaa atgaacccct gcgttagtta 750 caaaggaaac caatgccacttttgtttata agaccagaag gtagactttc 800 taagcataga tatttattga taacatttcattgtaactgg tgttctatac 850 acagaaaaca atttattttt taaataattg tctttttccataaaaaagat 900 tactttccat tcctttaggg gaaaaaaccc ctaaatagct tcatgtttcc950 ataatcagta ctttatattt ataaatgtat ttattattat tataagactg 1000cattttattt atatcatttt attaatatgg atttatttat agaaacatca 1050 ttcgatattgctacttgagt gtaaggctaa tattgatatt tatgacaata 1100 attatagagc tataacatgtttatttgacc tcaataaaca cttggatatc 1150 cc 1152 154 179 PRT Homo Sapien154 Met Ala Ala Leu Gln Lys Ser Val Ser Ser Phe Leu Met Gly Thr 1 5 1015 Leu Ala Thr Ser Cys Leu Leu Leu Leu Ala Leu Leu Val Gln Gly 20 25 30Gly Ala Ala Ala Pro Ile Ser Ser His Cys Arg Leu Asp Lys Ser 35 40 45 AsnPhe Gln Gln Pro Tyr Ile Thr Asn Arg Thr Phe Met Leu Ala 50 55 60 Lys GluAla Ser Leu Ala Asp Asn Asn Thr Asp Val Arg Leu Ile 65 70 75 Gly Glu LysLeu Phe His Gly Val Ser Met Ser Glu Arg Cys Tyr 80 85 90 Leu Met Lys GlnVal Leu Asn Phe Thr Leu Glu Glu Val Leu Phe 95 100 105 Pro Gln Ser AspArg Phe Gln Pro Tyr Met Gln Glu Val Val Pro 110 115 120 Phe Leu Ala ArgLeu Ser Asn Arg Leu Ser Thr Cys His Ile Glu 125 130 135 Gly Asp Asp LeuHis Ile Gln Arg Asn Val Gln Lys Leu Lys Asp 140 145 150 Thr Val Lys LysLeu Gly Glu Ser Gly Glu Ile Lys Ala Ile Gly 155 160 165 Glu Leu Asp LeuLeu Phe Met Ser Leu Arg Asn Ala Cys Ile 170 175 155 1320 DNA Homo Sapien155 ggcttgctga aaataaaatc aggactccta acctgctcca gtcagcctgc 50 ttccacgaggcctgtcagtc agtgcccgac ttgtgactga gtgtgcagtg 100 cccagcatgt accaggtcagtgcagagggc tgcctgaggg ctgtgctgag 150 agggagagga gcagagatgc tgctgagggtggagggaggc caagctgcca 200 ggtttggggc tgggggccaa gtggagtgag aaactgggatcccaggggga 250 gggtgcagat gagggagcga cccagattag gtgaggacag ttctctcatt300 agccttttcc tacaggtggt tgcattcttg gcaatggtca tgggaaccca 350cacctacagc cactggccca gctgctgccc cagcaaaggg caggacacct 400 ctgaggagctgctgaggtgg agcactgtgc ctgtgcctcc cctagagcct 450 gctaggccca accgccacccagagtcctgt agggccagtg aagatggacc 500 cctcaacagc agggccatct ccccctggagatatgagttg gacagagact 550 tgaaccggct cccccaggac ctgtaccacg cccgttgcctgtgcccgcac 600 tgcgtcagcc tacagacagg ctcccacatg gacccccggg gcaactcgga650 gctgctctac cacaaccaga ctgtcttcta caggcggcca tgccatggcg 700agaagggcac ccacaagggc tactgcctgg agcgcaggct gtaccgtgtt 750 tccttagcttgtgtgtgtgt gcggccccgt gtgatgggct agccggacct 800 gctggaggct ggtccctttttgggaaacct ggagccaggt gtacaaccac 850 ttgccatgaa gggccaggat gcccagatgcttggcccctg tgaagtgctg 900 tctggagcag caggatcccg ggacaggatg gggggctttggggaaaacct 950 gcacttctgc acattttgaa aagagcagct gctgcttagg gccgccggaa1000 gctggtgtcc tgtcattttc tctcaggaaa ggttttcaaa gttctgccca 1050tttctggagg ccaccactcc tgtctcttcc tcttttccca tcccctgcta 1100 ccctggcccagcacaggcac tttctagata tttccccctt gctggagaag 1150 aaagagcccc tggttttatttgtttgttta ctcatcactc agtgagcatc 1200 tactttgggt gcattctagt gtagttactagtcttttgac atggatgatt 1250 ctgaggagga agctgttatt gaatgtatag agatttatccaaataaatat 1300 ctttatttaa aaatgaaaaa 1320 156 177 PRT Homo Sapien 156Met Arg Glu Arg Pro Arg Leu Gly Glu Asp Ser Ser Leu Ile Ser 1 5 10 15Leu Phe Leu Gln Val Val Ala Phe Leu Ala Met Val Met Gly Thr 20 25 30 HisThr Tyr Ser His Trp Pro Ser Cys Cys Pro Ser Lys Gly Gln 35 40 45 Asp ThrSer Glu Glu Leu Leu Arg Trp Ser Thr Val Pro Val Pro 50 55 60 Pro Leu GluPro Ala Arg Pro Asn Arg His Pro Glu Ser Cys Arg 65 70 75 Ala Ser Glu AspGly Pro Leu Asn Ser Arg Ala Ile Ser Pro Trp 80 85 90 Arg Tyr Glu Leu AspArg Asp Leu Asn Arg Leu Pro Gln Asp Leu 95 100 105 Tyr His Ala Arg CysLeu Cys Pro His Cys Val Ser Leu Gln Thr 110 115 120 Gly Ser His Met AspPro Arg Gly Asn Ser Glu Leu Leu Tyr His 125 130 135 Asn Gln Thr Val PheTyr Arg Arg Pro Cys His Gly Glu Lys Gly 140 145 150 Thr His Lys Gly TyrCys Leu Glu Arg Arg Leu Tyr Arg Val Ser 155 160 165 Leu Ala Cys Val CysVal Arg Pro Arg Val Met Gly 170 175 157 1515 DNA Homo Sapien 157ccggcgatgt cgctcgtgct gctaagcctg gccgcgctgt gcaggagcgc 50 cgtaccccgagagccgaccg ttcaatgtgg ctctgaaact gggccatctc 100 cagagtggat gctacaacatgatctaatcc ccggagactt gagggacctc 150 cgagtagaac ctgttacaac tagtgttgcaacaggggact attcaatttt 200 gatgaatgta agctgggtac tccgggcaga tgccagcatccgcttgttga 250 aggccaccaa gatttgtgtg acgggcaaaa gcaacttcca gtcctacagc300 tgtgtgaggt gcaattacac agaggccttc cagactcaga ccagaccctc 350tggtggtaaa tggacatttt cctacatcgg cttccctgta gagctgaaca 400 cagtctatttcattggggcc cataatattc ctaatgcaaa tatgaatgaa 450 gatggccctt ccatgtctgtgaatttcacc tcaccaggct gcctagacca 500 cataatgaaa tataaaaaaa agtgtgtcaaggccggaagc ctgtgggatc 550 cgaacatcac tgcttgtaag aagaatgagg agacagtagaagtgaacttc 600 acaaccactc ccctgggaaa cagatacatg gctcttatcc aacacagcac650 tatcatcggg ttttctcagg tgtttgagcc acaccagaag aaacaaacgc 700gagcttcagt ggtgattcca gtgactgggg atagtgaagg tgctacggtg 750 cagctgactccatattttcc tacttgtggc agcgactgca tccgacataa 800 aggaacagtt gtgctctgcccacaaacagg cgtccctttc cctctggata 850 acaacaaaag caagccggga ggctggctgcctctcctcct gctgtctctg 900 ctggtggcca catgggtgct ggtggcaggg atctatctaatgtggaggca 950 cgaaaggatc aagaagactt ccttttctac caccacacta ctgcccccca1000 ttaaggttct tgtggtttac ccatctgaaa tatgtttcca tcacacaatt 1050tgttacttca ctgaatttct tcaaaaccat tgcagaagtg aggtcatcct 1100 tgaaaagtggcagaaaaaga aaatagcaga gatgggtcca gtgcagtggc 1150 ttgccactca aaagaaggcagcagacaaag tcgtcttcct tctttccaat 1200 gacgtcaaca gtgtgtgcga tggtacctgtggcaagagcg agggcagtcc 1250 cagtgagaac tctcaagacc tcttccccct tgcctttaaccttttctgca 1300 gtgatctaag aagccagatt catctgcaca aatacgtggt ggtctacttt1350 agagagattg atacaaaaga cgattacaat gctctcagtg tctgccccaa 1400gtaccacctc atgaaggatg ccactgcttt ctgtgcagaa cttctccatg 1450 tcaagcagcaggtgtcagca ggaaaaagat cacaagcctg ccacgatggc 1500 tgctgctcct tgtag 1515158 502 PRT Homo Sapien 158 Met Ser Leu Val Leu Leu Ser Leu Ala Ala LeuCys Arg Ser Ala 1 5 10 15 Val Pro Arg Glu Pro Thr Val Gln Cys Gly SerGlu Thr Gly Pro 20 25 30 Ser Pro Glu Trp Met Leu Gln His Asp Leu Ile ProGly Asp Leu 35 40 45 Arg Asp Leu Arg Val Glu Pro Val Thr Thr Ser Val AlaThr Gly 50 55 60 Asp Tyr Ser Ile Leu Met Asn Val Ser Trp Val Leu Arg AlaAsp 65 70 75 Ala Ser Ile Arg Leu Leu Lys Ala Thr Lys Ile Cys Val Thr Gly80 85 90 Lys Ser Asn Phe Gln Ser Tyr Ser Cys Val Arg Cys Asn Tyr Thr 95100 105 Glu Ala Phe Gln Thr Gln Thr Arg Pro Ser Gly Gly Lys Trp Thr 110115 120 Phe Ser Tyr Ile Gly Phe Pro Val Glu Leu Asn Thr Val Tyr Phe 125130 135 Ile Gly Ala His Asn Ile Pro Asn Ala Asn Met Asn Glu Asp Gly 140145 150 Pro Ser Met Ser Val Asn Phe Thr Ser Pro Gly Cys Leu Asp His 155160 165 Ile Met Lys Tyr Lys Lys Lys Cys Val Lys Ala Gly Ser Leu Trp 170175 180 Asp Pro Asn Ile Thr Ala Cys Lys Lys Asn Glu Glu Thr Val Glu 185190 195 Val Asn Phe Thr Thr Thr Pro Leu Gly Asn Arg Tyr Met Ala Leu 200205 210 Ile Gln His Ser Thr Ile Ile Gly Phe Ser Gln Val Phe Glu Pro 215220 225 His Gln Lys Lys Gln Thr Arg Ala Ser Val Val Ile Pro Val Thr 230235 240 Gly Asp Ser Glu Gly Ala Thr Val Gln Leu Thr Pro Tyr Phe Pro 245250 255 Thr Cys Gly Ser Asp Cys Ile Arg His Lys Gly Thr Val Val Leu 260265 270 Cys Pro Gln Thr Gly Val Pro Phe Pro Leu Asp Asn Asn Lys Ser 275280 285 Lys Pro Gly Gly Trp Leu Pro Leu Leu Leu Leu Ser Leu Leu Val 290295 300 Ala Thr Trp Val Leu Val Ala Gly Ile Tyr Leu Met Trp Arg His 305310 315 Glu Arg Ile Lys Lys Thr Ser Phe Ser Thr Thr Thr Leu Leu Pro 320325 330 Pro Ile Lys Val Leu Val Val Tyr Pro Ser Glu Ile Cys Phe His 335340 345 His Thr Ile Cys Tyr Phe Thr Glu Phe Leu Gln Asn His Cys Arg 350355 360 Ser Glu Val Ile Leu Glu Lys Trp Gln Lys Lys Lys Ile Ala Glu 365370 375 Met Gly Pro Val Gln Trp Leu Ala Thr Gln Lys Lys Ala Ala Asp 380385 390 Lys Val Val Phe Leu Leu Ser Asn Asp Val Asn Ser Val Cys Asp 395400 405 Gly Thr Cys Gly Lys Ser Glu Gly Ser Pro Ser Glu Asn Ser Gln 410415 420 Asp Leu Phe Pro Leu Ala Phe Asn Leu Phe Cys Ser Asp Leu Arg 425430 435 Ser Gln Ile His Leu His Lys Tyr Val Val Val Tyr Phe Arg Glu 440445 450 Ile Asp Thr Lys Asp Asp Tyr Asn Ala Leu Ser Val Cys Pro Lys 455460 465 Tyr His Leu Met Lys Asp Ala Thr Ala Phe Cys Ala Glu Leu Leu 470475 480 His Val Lys Gln Gln Val Ser Ala Gly Lys Arg Ser Gln Ala Cys 485490 495 His Asp Gly Cys Cys Ser Leu 500 159 535 DNA Homo Sapien 159agccaccagc gcaacatgac agtgaagacc ctgcatggcc cagccatggt 50 caagtacttgctgctgtcga tattggggct tgcctttctg agtgaggcgg 100 cagctcggaa aatccccaaagtaggacata cttttttcca aaagcctgag 150 agttgcccgc ctgtgccagg aggtagtatgaagcttgaca ttggcatcat 200 caatgaaaac cagcgcgttt ccatgtcacg taacatcgagagccgctcca 250 cctccccctg gaattacact gtcacttggg accccaaccg gtacccctcg300 gaagttgtac aggcccagtg taggaacttg ggctgcatca atgctcaagg 350aaaggaagac atctccatga attccgttcc catccagcaa gagaccctgg 400 tcgtccggaggaagcaccaa ggctgctctg tttctttcca gttggagaag 450 gtgctggtga ctgttggctgcacctgcgtc acccctgtca tccaccatgt 500 gcagtaagag gtgcatatcc actcagctgaagaag 535 160 163 PRT Homo Sapien 160 Met Thr Val Lys Thr Leu His GlyPro Ala Met Val Lys Tyr Leu 1 5 10 15 Leu Leu Ser Ile Leu Gly Leu AlaPhe Leu Ser Glu Ala Ala Ala 20 25 30 Arg Lys Ile Pro Lys Val Gly His ThrPhe Phe Gln Lys Pro Glu 35 40 45 Ser Cys Pro Pro Val Pro Gly Gly Ser MetLys Leu Asp Ile Gly 50 55 60 Ile Ile Asn Glu Asn Gln Arg Val Ser Met SerArg Asn Ile Glu 65 70 75 Ser Arg Ser Thr Ser Pro Trp Asn Tyr Thr Val ThrTrp Asp Pro 80 85 90 Asn Arg Tyr Pro Ser Glu Val Val Gln Ala Gln Cys ArgAsn Leu 95 100 105 Gly Cys Ile Asn Ala Gln Gly Lys Glu Asp Ile Ser MetAsn Ser 110 115 120 Val Pro Ile Gln Gln Glu Thr Leu Val Val Arg Arg LysHis Gln 125 130 135 Gly Cys Ser Val Ser Phe Gln Leu Glu Lys Val Leu ValThr Val 140 145 150 Gly Cys Thr Cys Val Thr Pro Val Ile His His Val Gln155 160 161 2380 DNA Homo Sapien 161 acactggcca aacaaaaacg aaagcactccgtgctggaag taggaggaga 50 gtcaggactc ccaggacaga gagtgcacaa actacccagcacagccccct 100 ccgccccctc tggaggctga agagggattc cagcccctgc cacccacaga150 cacgggctga ctggggtgtc tgcccccctt gggggggggc agcacagggc 200ctcaggcctg ggtgccacct ggcacctaga agatgcctgt gccctggttc 250 ttgctgtccttggcactggg ccgaagccca gtggtccttt ctctggagag 300 gcttgtgggg cctcaggacgctacccactg ctctccgggc ctctcctgcc 350 gcctctggga cagtgacata ctctgcctgcctggggacat cgtgcctgct 400 ccgggccccg tgctggcgcc tacgcacctg cagacagagctggtgctgag 450 gtgccagaag gagaccgact gtgacctctg tctgcgtgtg gctgtccact500 tggccgtgca tgggcactgg gaagagcctg aagatgagga aaagtttgga 550ggagcagctg actcaggggt ggaggagcct aggaatgcct ctctccaggc 600 ccaagtcgtgctctccttcc aggcctaccc tactgcccgc tgcgtcctgc 650 tggaggtgca agtgcctgctgcccttgtgc agtttggtca gtctgtgggc 700 tctgtggtat atgactgctt cgaggctgccctagggagtg aggtacgaat 750 ctggtcctat actcagccca ggtacgagaa ggaactcaaccacacacagc 800 agctgcctgc cctgccctgg ctcaacgtgt cagcagatgg tgacaacgtg850 catctggttc tgaatgtctc tgaggagcag cacttcggcc tctccctgta 900ctggaatcag gtccagggcc ccccaaaacc ccggtggcac aaaaacctga 950 ctggaccgcagatcattacc ttgaaccaca cagacctggt tccctgcctc 1000 tgtattcagg tgtggcctctggaacctgac tccgttagga cgaacatctg 1050 ccccttcagg gaggaccccc gcgcacaccagaacctctgg caagccgccc 1100 gactgcgact gctgaccctg cagagctggc tgctggacgcaccgtgctcg 1150 ctgcccgcag aagcggcact gtgctggcgg gctccgggtg gggacccctg1200 ccagccactg gtcccaccgc tttcctggga gaacgtcact gtggacaagg 1250ttctcgagtt cccattgctg aaaggccacc ctaacctctg tgttcaggtg 1300 aacagctcggagaagctgca gctgcaggag tgcttgtggg ctgactccct 1350 ggggcctctc aaagacgatgtgctactgtt ggagacacga ggcccccagg 1400 acaacagatc cctctgtgcc ttggaacccagtggctgtac ttcactaccc 1450 agcaaagcct ccacgagggc agctcgcctt ggagagtacttactacaaga 1500 cctgcagtca ggccagtgtc tgcagctatg ggacgatgac ttgggagcgc1550 tatgggcctg ccccatggac aaatacatcc acaagcgctg ggccctcgtg 1600tggctggcct gcctactctt tgccgctgcg ctttccctca tcctccttct 1650 caaaaaggatcacgcgaaag ggtggctgag gctcttgaaa caggacgtcc 1700 gctcgggggc ggccgccaggggccgcgcgg ctctgctcct ctactcagcc 1750 gatgactcgg gtttcgagcg cctggtgggcgccctggcgt cggccctgtg 1800 ccagctgccg ctgcgcgtgg ccgtagacct gtggagccgtcgtgaactga 1850 gcgcgcaggg gcccgtggct tggtttcacg cgcagcggcg ccagaccctg1900 caggagggcg gcgtggtggt cttgctcttc tctcccggtg cggtggcgct 1950gtgcagcgag tggctacagg atggggtgtc cgggcccggg gcgcacggcc 2000 cgcacgacgccttccgcgcc tcgctcagct gcgtgctgcc cgacttcttg 2050 cagggccggg cgcccggcagctacgtgggg gcctgcttcg acaggctgct 2100 ccacccggac gccgtacccg cccttttccgcaccgtgccc gtcttcacac 2150 tgccctccca actgccagac ttcctggggg ccctgcagcagcctcgcgcc 2200 ccgcgttccg ggcggctcca agagagagcg gagcaagtgt cccgggccct2250 tcagccagcc ctggatagct acttccatcc cccggggact cccgcgccgg 2300gacgcggggt gggaccaggg gcgggacctg gggcggggga cgggacttaa 2350 ataaaggcagacgctgtttt tctaaaaaaa 2380 162 705 PRT Homo Sapien 162 Met Pro Val ProTrp Phe Leu Leu Ser Leu Ala Leu Gly Arg Ser 1 5 10 15 Pro Val Val LeuSer Leu Glu Arg Leu Val Gly Pro Gln Asp Ala 20 25 30 Thr His Cys Ser ProGly Leu Ser Cys Arg Leu Trp Asp Ser Asp 35 40 45 Ile Leu Cys Leu Pro GlyAsp Ile Val Pro Ala Pro Gly Pro Val 50 55 60 Leu Ala Pro Thr His Leu GlnThr Glu Leu Val Leu Arg Cys Gln 65 70 75 Lys Glu Thr Asp Cys Asp Leu CysLeu Arg Val Ala Val His Leu 80 85 90 Ala Val His Gly His Trp Glu Glu ProGlu Asp Glu Glu Lys Phe 95 100 105 Gly Gly Ala Ala Asp Ser Gly Val GluGlu Pro Arg Asn Ala Ser 110 115 120 Leu Gln Ala Gln Val Val Leu Ser PheGln Ala Tyr Pro Thr Ala 125 130 135 Arg Cys Val Leu Leu Glu Val Gln ValPro Ala Ala Leu Val Gln 140 145 150 Phe Gly Gln Ser Val Gly Ser Val ValTyr Asp Cys Phe Glu Ala 155 160 165 Ala Leu Gly Ser Glu Val Arg Ile TrpSer Tyr Thr Gln Pro Arg 170 175 180 Tyr Glu Lys Glu Leu Asn His Thr GlnGln Leu Pro Ala Leu Pro 185 190 195 Trp Leu Asn Val Ser Ala Asp Gly AspAsn Val His Leu Val Leu 200 205 210 Asn Val Ser Glu Glu Gln His Phe GlyLeu Ser Leu Tyr Trp Asn 215 220 225 Gln Val Gln Gly Pro Pro Lys Pro ArgTrp His Lys Asn Leu Thr 230 235 240 Gly Pro Gln Ile Ile Thr Leu Asn HisThr Asp Leu Val Pro Cys 245 250 255 Leu Cys Ile Gln Val Trp Pro Leu GluPro Asp Ser Val Arg Thr 260 265 270 Asn Ile Cys Pro Phe Arg Glu Asp ProArg Ala His Gln Asn Leu 275 280 285 Trp Gln Ala Ala Arg Leu Arg Leu LeuThr Leu Gln Ser Trp Leu 290 295 300 Leu Asp Ala Pro Cys Ser Leu Pro AlaGlu Ala Ala Leu Cys Trp 305 310 315 Arg Ala Pro Gly Gly Asp Pro Cys GlnPro Leu Val Pro Pro Leu 320 325 330 Ser Trp Glu Asn Val Thr Val Asp LysVal Leu Glu Phe Pro Leu 335 340 345 Leu Lys Gly His Pro Asn Leu Cys ValGln Val Asn Ser Ser Glu 350 355 360 Lys Leu Gln Leu Gln Glu Cys Leu TrpAla Asp Ser Leu Gly Pro 365 370 375 Leu Lys Asp Asp Val Leu Leu Leu GluThr Arg Gly Pro Gln Asp 380 385 390 Asn Arg Ser Leu Cys Ala Leu Glu ProSer Gly Cys Thr Ser Leu 395 400 405 Pro Ser Lys Ala Ser Thr Arg Ala AlaArg Leu Gly Glu Tyr Leu 410 415 420 Leu Gln Asp Leu Gln Ser Gly Gln CysLeu Gln Leu Trp Asp Asp 425 430 435 Asp Leu Gly Ala Leu Trp Ala Cys ProMet Asp Lys Tyr Ile His 440 445 450 Lys Arg Trp Ala Leu Val Trp Leu AlaCys Leu Leu Phe Ala Ala 455 460 465 Ala Leu Ser Leu Ile Leu Leu Leu LysLys Asp His Ala Lys Gly 470 475 480 Trp Leu Arg Leu Leu Lys Gln Asp ValArg Ser Gly Ala Ala Ala 485 490 495 Arg Gly Arg Ala Ala Leu Leu Leu TyrSer Ala Asp Asp Ser Gly 500 505 510 Phe Glu Arg Leu Val Gly Ala Leu AlaSer Ala Leu Cys Gln Leu 515 520 525 Pro Leu Arg Val Ala Val Asp Leu TrpSer Arg Arg Glu Leu Ser 530 535 540 Ala Gln Gly Pro Val Ala Trp Phe HisAla Gln Arg Arg Gln Thr 545 550 555 Leu Gln Glu Gly Gly Val Val Val LeuLeu Phe Ser Pro Gly Ala 560 565 570 Val Ala Leu Cys Ser Glu Trp Leu GlnAsp Gly Val Ser Gly Pro 575 580 585 Gly Ala His Gly Pro His Asp Ala PheArg Ala Ser Leu Ser Cys 590 595 600 Val Leu Pro Asp Phe Leu Gln Gly ArgAla Pro Gly Ser Tyr Val 605 610 615 Gly Ala Cys Phe Asp Arg Leu Leu HisPro Asp Ala Val Pro Ala 620 625 630 Leu Phe Arg Thr Val Pro Val Phe ThrLeu Pro Ser Gln Leu Pro 635 640 645 Asp Phe Leu Gly Ala Leu Gln Gln ProArg Ala Pro Arg Ser Gly 650 655 660 Arg Leu Gln Glu Arg Ala Glu Gln ValSer Arg Ala Leu Gln Pro 665 670 675 Ala Leu Asp Ser Tyr Phe His Pro ProGly Thr Pro Ala Pro Gly 680 685 690 Arg Gly Val Gly Pro Gly Ala Gly ProGly Ala Gly Asp Gly Thr 695 700 705 163 2478 DNA Homo Sapien 163gtcagtgcgg gaggccggtc agccaccaag atgactgaca ggttcagctc 50 tctgcagcacactaccctca agccacctga tgtgacctgt atctccaaag 100 tgagatcgat tcagatgattgttcatccta cccccacgcc aatccgtgca 150 ggcgatggcc accggctaac cctggaagacatcttccatg acctgttcta 200 ccacttagag ctccaggtca accgcaccta ccaaatgcaccttggaggga 250 agcagagaga atatgagttc ttcggcctga cccctgacac agagttcctt300 ggcaccatca tgatttgcgt tcccacctgg gccaaggaga gtgcccccta 350catgtgccga gtgaagacac tgccagaccg gacatggacc tactccttct 400 ccggagccttcctgttctcc atgggcttcc tcgtcgcagt actctgctac 450 ctgagctaca gatatgtcaccaagccgcct gcacctccca actccctgaa 500 cgtccagcga gtcctgactt tccagccgctgcgcttcatc caggagcacg 550 tcctgatccc tgtctttgac ctcagcggcc ccagcagtctggcccagcct 600 gtccagtact cccagatcag ggtgtctgga cccagggagc ccgcaggagc650 tccacagcgg catagcctgt ccgagatcac ctacttaggg cagccagaca 700tctccatcct ccagccctcc aacgtgccac ctccccagat cctctcccca 750 ctgtcctatgccccaaacgc tgcccctgag gtcgggcccc catcctatgc 800 acctcaggtg acccccgaagctcaattccc attctacgcc ccacaggcca 850 tctctaaggt ccagccttcc tcctatgcccctcaagccac tccggacagc 900 tggcctccct cctatggggt atgcatggaa ggttctggcaaagactcccc 950 cactgggaca ctttctagtc ctaaacacct taggcctaaa ggtcagcttc1000 agaaagagcc accagctgga agctgcatgt taggtggcct ttctctgcag 1050gaggtgacct ccttggctat ggaggaatcc caagaagcaa aatcattgca 1100 ccagcccctggggatttgca cagacagaac atctgaccca aatgtgctac 1150 acagtgggga ggaagggacaccacagtacc taaagggcca gctccccctc 1200 ctctcctcag tccagatcga gggccaccccatgtccctcc ctttgcaacc 1250 tccttccggt ccatgttccc cctcggacca aggtccaagtccctggggcc 1300 tgctggagtc ccttgtgtgt cccaaggatg aagccaagag cccagcccct1350 gagacctcag acctggagca gcccacagaa ctggattctc ttttcagagg 1400cctggccctg actgtgcagt gggagtcctg aggggaatgg gaaaggcttg 1450 gtgcttcctccctgtcccta cccagtgtca catccttggc tgtcaatccc 1500 atgcctgccc atgccacacactctgcgatc tggcctcaga cgggtgccct 1550 tgagagaagc agagggagtg gcatgcagggcccctgccat gggtgcgctc 1600 ctcaccggaa caaagcagca tgataaggac tgcagcgggggagctctggg 1650 gagcagcttg tgtagacaag cgcgtgctcg ctgagccctg caaggcagaa1700 atgacagtgc aaggaggaaa tgcagggaaa ctcccgaggt ccagagcccc 1750acctcctaac accatggatt caaagtgctc agggaatttg cctctccttg 1800 ccccattcctggccagtttc acaatctagc tcgacagagc atgaggcccc 1850 tgcctcttct gtcattgttcaaaggtggga agagagcctg gaaaagaacc 1900 aggcctggaa aagaaccaga aggaggctgggcagaaccag aacaacctgc 1950 acttctgcca aggccagggc cagcaggacg gcaggactctagggaggggt 2000 gtggcctgca gctcattccc agccagggca actgcctgac gttgcacgat2050 ttcagcttca ttcctctgat agaacaaagc gaaatgcagg tccaccaggg 2100agggagacac acaagccttt tctgcaggca ggagtttcag accctatcct 2150 gagaatggggtttgaaagga aggtgagggc tgtggcccct ggacgggtac 2200 aataacacac tgtactgatgtcacaacttt gcaagctctg ccttgggttc 2250 agcccatctg ggctcaaatt ccagcctcaccactcacaag ctgtgtgact 2300 tcaaacaaat gaaatcagtg cccagaacct cggtttcctcatctgtaatg 2350 tggggatcat aacacctacc tcatggagtt gtggtgaaga tgaaatgaag2400 tcatgtcttt aaagtgctta atagtgcctg gtacatgggc agtgcccaat 2450aaacggtagc tatttaaaaa aaaaaaaa 2478 164 574 PRT Homo Sapien 164 Met ArgThr Leu Leu Thr Ile Leu Thr Val Gly Ser Leu Ala Ala 1 5 10 15 His AlaPro Glu Asp Pro Ser Asp Leu Leu Gln His Val Lys Phe 20 25 30 Gln Ser SerAsn Phe Glu Asn Ile Leu Thr Trp Asp Ser Gly Pro 35 40 45 Glu Gly Thr ProAsp Thr Val Tyr Ser Ile Glu Tyr Lys Thr Tyr 50 55 60 Gly Glu Arg Asp TrpVal Ala Lys Lys Gly Cys Gln Arg Ile Thr 65 70 75 Arg Lys Ser Cys Asn LeuThr Val Glu Thr Gly Asn Leu Thr Glu 80 85 90 Leu Tyr Tyr Ala Arg Val ThrAla Val Ser Ala Gly Gly Arg Ser 95 100 105 Ala Thr Lys Met Thr Asp ArgPhe Ser Ser Leu Gln His Thr Thr 110 115 120 Leu Lys Pro Pro Asp Val ThrCys Ile Ser Lys Val Arg Ser Ile 125 130 135 Gln Met Ile Val His Pro ThrPro Thr Pro Ile Arg Ala Gly Asp 140 145 150 Gly His Arg Leu Thr Leu GluAsp Ile Phe His Asp Leu Phe Tyr 155 160 165 His Leu Glu Leu Gln Val AsnArg Thr Tyr Gln Met His Leu Gly 170 175 180 Gly Lys Gln Arg Glu Tyr GluPhe Phe Gly Leu Thr Pro Asp Thr 185 190 195 Glu Phe Leu Gly Thr Ile MetIle Cys Val Pro Thr Trp Ala Lys 200 205 210 Glu Ser Ala Pro Tyr Met CysArg Val Lys Thr Leu Pro Asp Arg 215 220 225 Thr Trp Thr Tyr Ser Phe SerGly Ala Phe Leu Phe Ser Met Gly 230 235 240 Phe Leu Val Ala Val Leu CysTyr Leu Ser Tyr Arg Tyr Val Thr 245 250 255 Lys Pro Pro Ala Pro Pro AsnSer Leu Asn Val Gln Arg Val Leu 260 265 270 Thr Phe Gln Pro Leu Arg PheIle Gln Glu His Val Leu Ile Pro 275 280 285 Val Phe Asp Leu Ser Gly ProSer Ser Leu Ala Gln Pro Val Gln 290 295 300 Tyr Ser Gln Ile Arg Val SerGly Pro Arg Glu Pro Ala Gly Ala 305 310 315 Pro Gln Arg His Ser Leu SerGlu Ile Thr Tyr Leu Gly Gln Pro 320 325 330 Asp Ile Ser Ile Leu Gln ProSer Asn Val Pro Pro Pro Gln Ile 335 340 345 Leu Ser Pro Leu Ser Tyr AlaPro Asn Ala Ala Pro Glu Val Gly 350 355 360 Pro Pro Ser Tyr Ala Pro GlnVal Thr Pro Glu Ala Gln Phe Pro 365 370 375 Phe Tyr Ala Pro Gln Ala IleSer Lys Val Gln Pro Ser Ser Tyr 380 385 390 Ala Pro Gln Ala Thr Pro AspSer Trp Pro Pro Ser Tyr Gly Val 395 400 405 Cys Met Glu Gly Ser Gly LysAsp Ser Pro Thr Gly Thr Leu Ser 410 415 420 Ser Pro Lys His Leu Arg ProLys Gly Gln Leu Gln Lys Glu Pro 425 430 435 Pro Ala Gly Ser Cys Met LeuGly Gly Leu Ser Leu Gln Glu Val 440 445 450 Thr Ser Leu Ala Met Glu GluSer Gln Glu Ala Lys Ser Leu His 455 460 465 Gln Pro Leu Gly Ile Cys ThrAsp Arg Thr Ser Asp Pro Asn Val 470 475 480 Leu His Ser Gly Glu Glu GlyThr Pro Gln Tyr Leu Lys Gly Gln 485 490 495 Leu Pro Leu Leu Ser Ser ValGln Ile Glu Gly His Pro Met Ser 500 505 510 Leu Pro Leu Gln Pro Pro SerGly Pro Cys Ser Pro Ser Asp Gln 515 520 525 Gly Pro Ser Pro Trp Gly LeuLeu Glu Ser Leu Val Cys Pro Lys 530 535 540 Asp Glu Ala Lys Ser Pro AlaPro Glu Thr Ser Asp Leu Glu Gln 545 550 555 Pro Thr Glu Leu Asp Ser LeuPhe Arg Gly Leu Ala Leu Thr Val 560 565 570 Gln Trp Glu Ser 165 1060 DNAHomo Sapien 165 tggcctactg gaaaaaaaaa aaaaaaaaaa aaaagtcacc cgggcccgcg50 gtggccacaa catggctgcg gcgccggggc tgctcttctg gctgttcgtg 100 ctgggggcgctctggtgggt cccgggccag tcggatctca gccacggacg 150 gcgtttctcg gacctcaaagtgtgcgggga cgaagagtgc agcatgttaa 200 tgtaccgtgg gaaagctctt gaagacttcacgggccctga ttgtcgtttt 250 gtgaatttta aaaaaggtga cgatgtatat gtctactacaaactggcagg 300 gggatccctt gaactttggg ctggaagtgt tgaacacagt tttggatatt350 ttccaaaaga tttgatcaag gtacttcata aatacacgga agaagagcta 400catattccag cagatgagac agactttgtc tgctttgaag gaggaagaga 450 tgattttaatagttataatg tagaagagct tttaggatct ttggaactgg 500 aggactctgt acctgaagagtcgaagaaag ctgaagaagt ttctcagcac 550 agagagaaat ctcctgagga gtctcgggggcgtgaacttg accctgtgcc 600 tgagcccgag gcattcagag ctgattcaga ggatggagaaggtgctttct 650 cagagagcac cgaggggctg cagggacagc cctcagctca ggagagccac700 cctcacacca gcggtcctgc ggctaacgct cagggagtgc agtcttcgtt 750ggacactttt gaagaaattc tgcacgataa attgaaagtg ccgggaagcg 800 aaagcagaactggcaatagt tctcctgcct cggtggagcg ggagaagaca 850 gatgcttaca aagtcctgaaaacagaaatg agtcagagag gaagtggaca 900 gtgcgttatt cattacagca aaggatttcgttggcatcaa aatctaagtt 950 tgttttacaa agattgtttt tagtactaag ctgccttggcagtttgcatt 1000 tttgagccaa acaaaaatat attattttcc cttctaagta aaaaaaaaaa1050 aaaaaaaaaa 1060 166 303 PRT Homo Sapien 166 Met Ala Ala Ala Pro GlyLeu Leu Phe Trp Leu Phe Val Leu Gly 1 5 10 15 Ala Leu Trp Trp Val ProGly Gln Ser Asp Leu Ser His Gly Arg 20 25 30 Arg Phe Ser Asp Leu Lys ValCys Gly Asp Glu Glu Cys Ser Met 35 40 45 Leu Met Tyr Arg Gly Lys Ala LeuGlu Asp Phe Thr Gly Pro Asp 50 55 60 Cys Arg Phe Val Asn Phe Lys Lys GlyAsp Asp Val Tyr Val Tyr 65 70 75 Tyr Lys Leu Ala Gly Gly Ser Leu Glu LeuTrp Ala Gly Ser Val 80 85 90 Glu His Ser Phe Gly Tyr Phe Pro Lys Asp LeuIle Lys Val Leu 95 100 105 His Lys Tyr Thr Glu Glu Glu Leu His Ile ProAla Asp Glu Thr 110 115 120 Asp Phe Val Cys Phe Glu Gly Gly Arg Asp AspPhe Asn Ser Tyr 125 130 135 Asn Val Glu Glu Leu Leu Gly Ser Leu Glu LeuGlu Asp Ser Val 140 145 150 Pro Glu Glu Ser Lys Lys Ala Glu Glu Val SerGln His Arg Glu 155 160 165 Lys Ser Pro Glu Glu Ser Arg Gly Arg Glu LeuAsp Pro Val Pro 170 175 180 Glu Pro Glu Ala Phe Arg Ala Asp Ser Glu AspGly Glu Gly Ala 185 190 195 Phe Ser Glu Ser Thr Glu Gly Leu Gln Gly GlnPro Ser Ala Gln 200 205 210 Glu Ser His Pro His Thr Ser Gly Pro Ala AlaAsn Ala Gln Gly 215 220 225 Val Gln Ser Ser Leu Asp Thr Phe Glu Glu IleLeu His Asp Lys 230 235 240 Leu Lys Val Pro Gly Ser Glu Ser Arg Thr GlyAsn Ser Ser Pro 245 250 255 Ala Ser Val Glu Arg Glu Lys Thr Asp Ala TyrLys Val Leu Lys 260 265 270 Thr Glu Met Ser Gln Arg Gly Ser Gly Gln CysVal Ile His Tyr 275 280 285 Ser Lys Gly Phe Arg Trp His Gln Asn Leu SerLeu Phe Tyr Lys 290 295 300 Asp Cys Phe 167 2570 DNA Homo Sapien 167ccaggaccag ggcgcaccgg ctcagcctct cacttgtcag aggccgggga 50 agagaagcaaagcgcaacgg tgtggtccaa gccggggctt ctgcttcgcc 100 tctaggacat acacgggaccccctaacttc agtcccccaa acgcgcaccc 150 tcgaagtctt gaactccagc cccgcacatccacgcgcggc acaggcgcgg 200 caggcggcag gtcccggccg aaggcgatgc gcgcagggggtcgggcagct 250 gggctcgggc ggcgggagta gggcccggca gggaggcagg gaggctgcat300 attcagagtc gcgggctgcg ccctgggcag aggccgccct cgctccacgc 350aacacctgct gctgccaccg cgccgcgatg agccgcgtgg tctcgctgct 400 gctgggcgccgcgctgctct gcggccacgg agccttctgc cgccgcgtgg 450 tcagcggcca aaaggtgtgttttgctgact tcaagcatcc ctgctacaaa 500 atggcctact tccatgaact gtccagccgagtgagctttc aggaggcacg 550 cctggcttgt gagagtgagg gaggagtcct cctcagccttgagaatgaag 600 cagaacagaa gttaatagag agcatgttgc aaaacctgac aaaacccggg650 acagggattt ctgatggtga tttctggata gggctttgga ggaatggaga 700tgggcaaaca tctggtgcct gcccagatct ctaccagtgg tctgatggaa 750 gcaattcccagtaccgaaac tggtacacag atgaaccttc ctgcggaagt 800 gaaaagtgtg ttgtgatgtatcaccaacca actgccaatc ctggccttgg 850 gggtccctac ctttaccagt ggaatgatgacaggtgtaac atgaagcaca 900 attatatttg caagtatgaa ccagagatta atccaacagcccctgtagaa 950 aagccttatc ttacaaatca accaggagac acccatcaga atgtggttgt1000 tactgaagca ggtataattc ccaatctaat ttatgttgtt ataccaacaa 1050tacccctgct cttactgata ctggttgctt ttggaacctg ttgtttccag 1100 atgctgcataaaagtaaagg aagaacaaaa actagtccaa accagtctac 1150 actgtggatt tcaaagagtaccagaaaaga aagtggcatg gaagtataat 1200 aactcattga cttggttcca gaattttgtaattctggatc tgtataagga 1250 atggcatcag aacaatagct tggaatggct tgaaatcacaaaggatctgc 1300 aagatgaact gtaagctccc ccttgaggca aatattaaag taatttttat1350 atgtctatta tttcatttaa agaatatgct gtgctaataa tggagtgaga 1400catgcttatt ttgctaaagg atgcacccaa acttcaaact tcaagcaaat 1450 gaaatggacaatgcagataa agttgttatc aacacgtcgg gagtatgtgt 1500 gttagaagca attccttttatttctttcac ctttcataag ttgttatcta 1550 gtcaatgtaa tgtatattgt attgaaatttacagtgtgca aaagtatttt 1600 acctttgcat aagtgtttga taaaaatgaa ctgttctaatatttattttt 1650 atggcatctc atttttcaat acatgctctt ttgattaaag aaacttatta1700 ctgttgtcaa ctgaattcac acacacacaa atatagtacc atagaaaaag 1750tttgttttct cgaaataatt catctttcag cttctctgct tttggtcaat 1800 gtctaggaaatctcttcaga aataagaagc tatttcatta agtgtgatat 1850 aaacctcctc aaacattttacttagaggca aggattgtct aatttcaatt 1900 gtgcaagaca tgtgccttat aattatttttagcttaaaat taaacagatt 1950 ttgtaataat gtaactttgt taataggtgc ataaacactaatgcagtcaa 2000 tttgaacaaa agaagtgaca tacacaatat aaatcatatg tcttcacacg2050 ttgcctatat aatgagaagc agctctctga gggttctgaa atcaatgtgg 2100tccctctctt gcccactaaa caaagatggt tgttcggggt ttgggattga 2150 cactggaggcagatagttgc aaagttagtc taaggtttcc ctagctgtat 2200 ttagcctctg actatattagtatacaaaga ggtcatgtgg ttgagaccag 2250 gtgaatagtc actatcagtg tggagacaagcacagcacac agacatttta 2300 ggaaggaaag gaactacgaa atcgtgtgaa aatgggttggaacccatcag 2350 tgatcgcata ttcattgatg agggtttgct tgagatagaa aatggtggct2400 cctttctgtc ttatctccta gtttcttcaa tgcttacgcc ttgttcttct 2450caagagaaag ttgtaactct ctggtcttca tatgtccctg tgctcctttt 2500 aaccaaataaagagttcttg tttctggggg aaaaaaaaaa aaaaaaaaaa 2550 aaaaaaaaaa aaaaaaaaaa2570 168 273 PRT Homo Sapien 168 Met Ser Arg Val Val Ser Leu Leu Leu GlyAla Ala Leu Leu Cys 1 5 10 15 Gly His Gly Ala Phe Cys Arg Arg Val ValSer Gly Gln Lys Val 20 25 30 Cys Phe Ala Asp Phe Lys His Pro Cys Tyr LysMet Ala Tyr Phe 35 40 45 His Glu Leu Ser Ser Arg Val Ser Phe Gln Glu AlaArg Leu Ala 50 55 60 Cys Glu Ser Glu Gly Gly Val Leu Leu Ser Leu Glu AsnGlu Ala 65 70 75 Glu Gln Lys Leu Ile Glu Ser Met Leu Gln Asn Leu Thr LysPro 80 85 90 Gly Thr Gly Ile Ser Asp Gly Asp Phe Trp Ile Gly Leu Trp Arg95 100 105 Asn Gly Asp Gly Gln Thr Ser Gly Ala Cys Pro Asp Leu Tyr Gln110 115 120 Trp Ser Asp Gly Ser Asn Ser Gln Tyr Arg Asn Trp Tyr Thr Asp125 130 135 Glu Pro Ser Cys Gly Ser Glu Lys Cys Val Val Met Tyr His Gln140 145 150 Pro Thr Ala Asn Pro Gly Leu Gly Gly Pro Tyr Leu Tyr Gln Trp155 160 165 Asn Asp Asp Arg Cys Asn Met Lys His Asn Tyr Ile Cys Lys Tyr170 175 180 Glu Pro Glu Ile Asn Pro Thr Ala Pro Val Glu Lys Pro Tyr Leu185 190 195 Thr Asn Gln Pro Gly Asp Thr His Gln Asn Val Val Val Thr Glu200 205 210 Ala Gly Ile Ile Pro Asn Leu Ile Tyr Val Val Ile Pro Thr Ile215 220 225 Pro Leu Leu Leu Leu Ile Leu Val Ala Phe Gly Thr Cys Cys Phe230 235 240 Gln Met Leu His Lys Ser Lys Gly Arg Thr Lys Thr Ser Pro Asn245 250 255 Gln Ser Thr Leu Trp Ile Ser Lys Ser Thr Arg Lys Glu Ser Gly260 265 270 Met Glu Val 169 43 DNA Artificial Sequence Syntheticoligonucleotide probe 169 tgtaaaacga cggccagtta aatagacctg caattattaatct 43 170 41 DNA Artificial Sequence Synthetic oligonucleotide probe170 caggaaacag ctatgaccac ctgcacacct gcaaatccat t 41

1. An antibody that binds to the polypeptide shown in FIG. 136 (SEQ IDNO:136).
 2. The antibody of claim 1 which is a monoclonal antibody. 3.The antibody of claim 1 which is a humanized antibody.
 4. The antibodyof claim 1 which is an antibody fragment.
 5. The antibody of claim 1which is labeled.
 6. The antibody of claim 1 which specifically binds tothe polypeptide shown in FIG 136 (SEQ ID NO:136).